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Review

Connecting the Dots: Mitochondrial Dysfunction, PCOS, and Insulin Resistance—Insights and Therapeutic Advances

by
Samia Palat Tharayil
and
Pallavi Shukla
*
Department of Molecular Endocrinology, The Indian Council of Medical Research-National Institute for Research in Reproductive and Child Health (ICMR-NIRRCH), J.M. Street, Parel, Mumbai 400012, India
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(13), 6233; https://doi.org/10.3390/ijms26136233
Submission received: 19 April 2025 / Revised: 2 June 2025 / Accepted: 5 June 2025 / Published: 28 June 2025
(This article belongs to the Special Issue Advances in Insulin Resistance Research: 2nd Edition)

Abstract

Insulin resistance (IR) frequently develops in women with polycystic ovary syndrome (PCOS), an endocrinological disorder typified by hyperandrogenaemia, erratic menstrual cycles, and the presence of multiple cysts in the ovaries. It results in elevated androgen production contributing to the clinical manifestations of the syndrome including associated co-morbidities such as obesity and type 2 diabetes (T2D). Mounting data suggest the involvement of free fatty acids, reactive oxygen species (ROS) signalling, and mitochondrial dysfunction with IR. In recent years, numerous reports have suggested that mitochondrial dysregulation is associated with the pathogenesis of PCOS. Increased ROS, mutations/variants in mitochondrial DNA (mtDNA), and the altered expression of nuclear-related mitochondrial genes in insulin-resistant women with PCOS provide sufficient evidence for mitochondrial dysfunction as one of the factors contributing to PCOS pathogenesis. Despite the advancements in the field of interconnecting links between mitochondrial dysfunction, IR, and PCOS, various underlying mechanisms needs to be elucidated. Advancements in therapeutic interventions showed promising results in improving mitochondrial functions and IR in PCOS pathogenesis, including evolving mitochondrial transfer approaches that may improve in vitro fertilisation (IVF) outcomes in obese and insulin-resistant women with PCOS in future.

1. Introduction

Polycystic ovary syndrome (PCOS) is an endocrine dysfunction prevalent globally in 6–12% of women in their childbearing years. It is marked by erratic menstrual cycles, heightened androgen secretions, and the presence of multiple cysts in the ovaries. PCOS also predisposes women to many co-morbidities, in particular, obesity, metabolic syndrome (MetS), type 2 diabetes (T2D), cardiovascular diseases (CVDs), and endometrial cancer (EC) over time [1,2,3]. While the exact contributors of PCOS are still not fully characterised, insulin resistance (IR) and bad lifestyle/dietary factors coupled with genetic predisposition has been identified as a significant determining factor [4]. Alterations in insulin receptor structure or function, leading to aberrant signalling pathways or heightened levels of insulin-binding antibodies, reduce the sensitivity of peripheral tissues to insulin, leading to IR [5]. Furthermore, factors such as obesity exacerbate IR and are implicated in the metabolic syndrome, a frequently observed phenomenon in PCOS [6]. Obstructive sleep apnoea (OSA) and depression observed in women with PCOS are associated with increased activity in the sympathetic nervous system. OSA is related to hyperinsulinemia and is exacerbated by obesity. OSA may accelerate PCOS symptoms and is related to metabolic and CVD in these women [4]. Weight gain is becoming more prevalent among women with PCOS, with rates reaching up to 88% [7,8]. A different study indicates that 75% of lean and 95% of obese women diagnosed with PCOS experience IR [9]. Moreover, reduced insulin sensitivity inevitably results in hyperinsulinemia, which in turn fosters the development of hyperandrogenism by exerting a chronic stimulus on the cells of the ovarian theca [10].
In women with PCOS, the aberrant secretion patterns of gonadotropins such as luteinizing hormone (LH) and follicle-stimulating hormone (FSH), as well as ovarian steroids, contribute to IR [11]. Insulin, in turn, stimulates androgen synthesis and enhances LH function. This results in the overproduction of testosterone, androstenedione, and dehydroepiandrosterone by the ovaries in PCOS patients, as demonstrated in previous study [12]. It is plausible that hyperandrogenism plays a significant part in the pathogenesis of serious endocrine and metabolic disturbances linked to PCOS. Women diagnosed with PCOS having reduced sex hormone-binding globulin (SHBG) levels are more prone to obesity, IR, T2D, hyperandrogenism, and cardiovascular disease (CVD) [13], primarily owing to prevailing IR [14,15].
Due to IR, women with PCOS have elevated blood sugar levels that put mitochondria under non-physiological stress, resulting in excessive reactive oxygen species (ROS) production. Moreover, mitochondrial DNA (mtDNA) lies in the proximity of electron transport chain (ETC) is susceptible to considerable damage due to oxidative stress (OS). In addition, due to a lack of efficient repair mechanisms, these mtDNA mutations can pile up and result in metabolic changes. Evolutionarily speaking, many loci in mitochondrial genome are conserved and cause small genetic variants to have significant ramifications in the pathogenesis of PCOS [16].
In this review, our aim is to reinforce the connections between insulin resistance, PCOS, and mitochondrial dysfunction by highlighting the robust association between PCOS and IR, emphasizing the role of mitochondrial dysfunction in both IR and PCOS, and this is supported by evidence of mtDNA variants associated with IR in PCOS. Additionally, we showcase advancements in therapies developed over the years to address mitochondrial dysfunction/OS and IR in women with PCOS.

2. Mitochondrial Biology

Mitochondria are double membrane-bound organelles containing a small circular genome (mtDNA) that is present in multiple copies in the cell [17,18]. There are roughly one to ten copies of mtDNA in each mitochondrion, with around 16,569 base pairs which codes for a displacement loop (D-Loop), 22 tRNAs, 2 rRNA, and 13 polypeptides required for RNA and protein synthesis [19,20]. The 13 polypeptides that are specified by mtDNA are subunits of complexes I through V, forms the mitochondrial respiratory chain are crucial for OXPHOS ATP synthesis [21]. D-loop, a non-coding sequence of mtDNA, contains regulatory components necessary for mtDNA transcription and replication [22]. The majority of the proteins of OXPHOS subunits are encoded by nuclear DNA, aside from their own genetic material. Compared to nuclear DNA, mtDNA is more prone to damage and mutation because it is not shielded by histones [18]. Mitochondrial biogenesis involves the coordinated synthesis of new proteins by both the nucleus and existing mitochondria to expand the cellular network of mitochondria. This process typically escalates in response to heightened energy requirements, such as during cellular proliferation. Furthermore, it could also ramp up to replace mitochondria damaged by the stressors of environment or OS [23]. Peroxisome proliferator-activated receptor-gamma co-activator α (PGC-1α), the principal regulator of biogenesis of mitochondria, is activated by phosphorylation in the nucleus stimulates string of transcription factors such as nuclear respiratory factor-1 (NRF-1), NRF-2, oestrogen-related receptor-a (ERR-a), and transcription factor A (TFAM). Out of these, NRF-1 enhances the transcription of nuclear genes responsible for controlling mitochondrial function, while NRF-2 boosts the transcription of genes crucial for redox homeostasis [24]. PGC-1 therefore increases the mitochondrial mass, as well as the capacity of mitochondrial oxidative phosphorylation [17]. TFAM is another factor that transcribes and replicates mtDNA [24]. Its expression is also regulated by NRF-1 [25]. However, the equilibrium of the cellular environment is maintained by a process known as mitophagy, which removes damaged mitochondria and its absence can result in a high number of dysfunctional mitochondria, impairing overall energy production. Furthermore, the accumulation of dysfunctional mitochondria can lead to the generation of ROS, triggering inflammation and signalling cell death. Generally, defective mitochondria are cleared via PTEN-induced putative kinase 1 and parkin-mediated mitophagy to control mitochondrial quality [17]. Mitochondria also have the ability to undergo both fusion and fission processes in order to sustain their functionality [26]. Mitochondrial fusion combines their contents, including DNA and metabolic substances, aiding in the restoration of damaged or depolarised membranes [27]. Three GTPases, namely mitofusin 1 and 2 (Mfn1/2) and optic atrophy1 (Opa1), situated on the outer and the inner membrane of the mitochondria, respectively, predominantly regulate this process [25,28,29]. The fusion of the outer membrane is mediated by mitofusin 1 and 2, while the fusion of inner membrane utilises optic atrophy protein [17]. Meanwhile, mitochondrial fission is regulated by the activity of Fis1 and dynamin-related protein 1 (DRP1), located on the outer membrane, which augment the quantity of mitochondria, preparing the cell for cellular division and meiosis [30]. Furthermore, mitochondria are also involved in the Ca2+-based signalling essential for diverse processes ranging from ATP production to cell death [31].

3. Role of Free Fatty Acids, ROS Signalling, and Mitochondrial Dysfunction in IR

An interdependent relationship exists between insulin and mitochondria, as insulin is required for mitochondrial fusion and mitochondria are needed to ensure proper insulin signalling [32,33]. Until now, two proposed mechanisms associate mitochondrial dysfunction with IR. One includes the partial oxidation of fatty acids, which contributes to fatty acid metabolites accumulation, resulting in the inhibition of insulin signalling and the other mechanism involves elevated ROS production due to electron leakage, a consequence of incomplete substrate oxidation. This impacts OS, leading to mitophagy and apoptosis, which, in turn, causes decreased substrate oxidation [34,35,36]. The first mechanism involves the incomplete oxidation of fatty acids such as diacylglycerol (DAG) and ceramide (CER), forming a plausible link between mitochondrial dysfunction and IR, as these supress insulin signalling by activating protein kinase C, which is translocated to the plasma membrane, resulting in insulin receptor [37] and protein kinase B (AKT) inhibition, respectively (Figure 1), [25,34,38]. The kinases activated by these lipid metabolites particularly impair insulin receptor substrate 1 (IRS1) [31,39]. In skeletal muscle, this impairment leads to a decrease in glucose transporter protein type-4 (GLUT4) expression and a subsequent decrease in cellular glucose uptake, further hampering the insulin signalling process [40]. Ectopic lipid build-up is predominantly seen in obesity and T2D as a particular initial change in the onset of IR [25,38]. The incompetency to store surplus energy in adipose tissue leads to an increased outflow of free fatty acids (FFAs) from fat stores into other tissues, such as skeletal muscle [41], causing metabolic dysregulation, including IR. Insufficient fatty acid oxidation resulting from mitochondrial dysfunction and/or decreased mitochondrial content further accumulates elevated levels of intracellular fatty acyl-CoA and DAG, which interfere with insulin signalling [42,43]. A study reported that in the adipose tissue of obese mice fed with a high-fat diet, reduced Mfn1/2 expressions and elevated Drp1 were observed, respectively. However, in the adipose tissue of obese humans only Mfn2 reduction was observed [44]. Moreover, in the skeletal muscle, an excess of FFA uptake increases the rate of beta-oxidation in obese individuals, causing mitochondria to become shorter and smaller due to heightened mitochondrial fission, thereby reducing its mass and function [45,46]. In another study, excess palmitate (PA) induced an increase in DRP1 and FIS1 (fission proteins) and the fragmentation of mitochondria in differentiated C2C12 muscle cells. Fragmentation resulted in heightened OS, mitochondrial dysfunction, and diminished insulin-stimulated glucose uptake [43]. Furthermore, it has been reported that peptides released during stress condition by mitochondria, such as apoptosis-inducing factor (AIF), impact insulin action. AIF is a peptide that forms part of complex I of ETC; when released from mitochondria, it induces chromatin condensation and DNA fragmentation in response to apoptotic signals [47]. Knocking out AIF in both the liver and muscles shielded mice from developing IR when exposed to a high-fat diet [48]. The impact of AIF deletion during insulin activity may occur through mechanisms akin to those of anti-diabetic drugs which inhibit complex I, or AIF might possess unrecognised signalling roles that affect cellular insulin activity [31]. Improvements in insulin sensitivity could be restored by increasing lipid oxidation, conferring protection against IR [40,49]. It has been reported that high glucose and FFAs increase the ROS generation by activation of NADPH oxidase 4 (NOX4), and their inhibition, along with monocyte chemotactic protein-1 (MCP-1) expression in differentiated adipocytes, reduces ROS production [50,51]. Moreover, the adipocyte-specific deficiency of NOX4 delays the onset of adipose inflammation and IR [52]. Meanwhile, the overexpression of NOX4 in excess overnutrition significantly reversed the inhibition of protein tyrosine phosphatase 1B (PTP1B), contributing to IR in adipocytes [46,53].
The result of incomplete substrate oxidation, which affects electron flow via the ETC and contributes to the generation of superoxide anions by reacting with molecular oxygen, is another plausible mechanism that connects mitochondrial dysfunction to IR. ROS generation damages various mitochondrial components such as DNA, proteins, and lipids [25]. In addition, the leakage of H2O2, which can readily pass the mitochondrial membrane, reaches these components, which, in the presence of Fe2+ ligands, can further generate OH radicals [43]. These produced OH radicals contribute to the inactivation of the components of enzymes involved in the tricarboxylic acid (TCA) cycle [43]. ROS initiates cellular signalling by modifying the thiol groups of the cysteine residues of the target protein, resulting in changes to the protein structure [43,54] and contributing to the overall OS [25]. Moreover, the elevated ROS levels enhance the phosphorylation of insulin receptors and IRS proteins and incite the aberrant activation of serine/threonine kinase signalling pathways, including c-Jun N-terminal kinase (JNK), nuclear factor kappa-B (NF-kB), and p38-mitogen-activated protein kinase (MAPK) [55]. Additionally, ROS also suppresses GLUT4 translocation in cells by affecting insulin signalling [56]. It is also known that insulin ensures proper mitochondrial functioning by maintaining NAD+/NADH ratio in ETC integrity by suppressing forkhead box 01 (FOXO1) and heme oxygenase-1 (HMOX1) [33,57]. It was also found that cultured cardiac muscle cells exposed to elevated glucose levels trigger the activation of NADPH oxidase 2 (NOX2), brought about by the activation of Ras-related C3 botulinum toxin substrate 1 (RAC1) and the translocation of the 7 kDa cytosolic subunit of NADPH oxidase (P47PHOX), leading to the production of ROS [58].
Apart from the aforementioned mechanisms, other factors involved in IR-associated mitochondrial dysfunction include altered calcium buffering capacity, the reduced expression of mitochondrial-associated ER membranes (MAMs), oxidative enzymes, ATP surplus, and sirtuin 1 (SIRT1) activity. Mitochondrial dysfunction alters Ca2+ buffering capacity, which is required for the activation of calcium/calmodulin kinase II (CaMKII); this in turn phosphorylates myosin-1c (Myo1c), which aids in transport of GLUT4 to the plasma membrane in response to insulin stimulation in adipocytes [59]. Altered Ca2+ levels could affect insulin-stimulated CaMKII activity and glucose transport action in these cells [31]. The points of physical connection between mitochondria and the endoplasmic reticulum (ER) are referred to as MAMs. The increased expression of MAM proteins demonstrated enhanced insulin sensitivity in the liver [60] and reduced the levels of cyclophilin-D, a mitochondrial protein, resulting in systemic IR and elevated blood glucose levels after administering pyruvate, which suggests heightened hepatic glucose production [60,61]. Additionally, inhibiting cyclophilin-D or removing MAM content disrupted the Ca2+ exchange between ER and mitochondrial cyclophilin-D knockout mice, leading to liver ER stress and mitochondrial dysfunction [62,63]. It has also been noted that IR follows ATP surplus, or the state in which ATP synthesis surpasses demand, in a number of tissues [64], leading to hyperinsulinemia and hyperglucagonemia. In order to reduce insulin sensitivity, it also activates and inhibits the mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) signalling pathways, respectively. Moreover, IR is facilitated by the decrease in AMPK activity brought on by mitophagy suppression [65]. According to a further study, individuals with T2D and insulin resistance with normal glucose tolerance have reduced expression of PGC-1α and 1ß [42,66,67]. Patients with T2D who were also obese showed a decreased activity of several mitochondrial oxidative enzymes [68,69]. Recently, it was observed that mitochondrial DNA methyltransferase 1 (DNMT1) and NAD+-dependent deacetylase SIRT1 have strong associations with IR [70,71,72]. It was shown that DNMT1 could be deacetylated by SIRT1, thus regulating the gene expression [73,74,75]. According to reports, insulin-resistant individuals have a considerably lower SIRT1 gene and protein expression in peripheral blood cells compared to insulin-sensitive individuals [72]. Furthermore, IR was shown to lower SIRT1 activity and cellular NAD+ levels in vivo [71,76].

4. IR in the Pathophysiology of PCOS

IR affects 38% to 95% of women diagnosed with PCOS, which is independent of obesity [36]. A study suggested that the impact of subcutaneous abdominal fat and visceral fat on IR differed, with subcutaneous fat protecting against IR and visceral fat causing IR by elevating FFA uptake in visceral adipocytes, in addition to non-adipose cells inducing lipotoxicity [77]; this would explain the incidence of lean women with PCOS and IR [18]. It is well established that PCOS is characterised by elevated testosterone and androstenedione levels, contributing to hyperandrogenism [78]. There are different mechanisms by which hyperinsulinemia aids androgen-induced anovulation. Insulin acts as a co-gonadotropin [79] and stimulates the effects of LH [80,81] on androgen biosynthesis in ovarian theca cells by inducing cytochrome P450c17 expression, which influences 17-hydroxylase and 17,20-lyase activity [56], making theca cells in women with PCOS more sensitive to the hyperandrogenic effects of insulin in contrast to healthy women [82]. Alternatively, there have been studies conducted in vivo and in vitro [83,84] which report that an excess of insulin inhibits SHBG release from the liver, thus elevating androgen levels [85] (Figure 1). This modification of SHBG levels enhances the bioavailability of free testosterone in the blood, thereby triggering heightened androgenic activity [85]. In addition to insulin, the anti-mullerian hormone (AMH), which is typically elevated in PCOS, also stimulates gonadotropin hormone-releasing hormone (GnRH) neurons, potentially promoting hyperandrogenism. Research indicates that daughters born to mothers with PCOS could potentially inherit a susceptibility due to abnormal exposure to androgens and AMH during gestation [85].
In a different study [86], women with PCOS exhibited lower kisspeptin serum levels, a peptide involved in puberty activation and GnRH pulsatile secretion during ovulation, when compared to controls. In addition, among PCOS subjects, the overweight or obese group exhibited lower levels of kisspeptin with negative correlations with homeostatic the model assessment of insulin resistance (HOMA-IR), body mass index (BMI), and androgens, thus suggesting that IR plays a role in reducing kisspeptin levels [87]. Although the association between IR and BMI in PCOS subjects remains divisive, it has been reported that non-obese PCOS women could have elevated IR regardless of BMI [88], whereas others suggest an association between IR and BMI [77,89,90]. IR and hyperandrogenism are also caused by inflammation due to the death of hypertrophic adipocytes [91,92]. IL-6 is also reported to reduce the activation of IRS1 and AKT [78]. Single nucleotide polymorphisms (SNPs) have been identified in proinflammatory cytokines genes, such as tumour necrosis factor (TNF), IL-6 [93], IL-10 [94], IL-17, and IL-32 [95], and act as a genotypic-specific predisposition to PCOS. Hormone leptin levels are also elevated in PCOS subjects, which in turn upregulate interferon–gamma (INF-gamma) and IL-6 production by binding with insulin receptor [96]. Meanwhile, adipokine omentin-1 [97] levels are lower in women with PCOS and IR [77,89,90]. Furthermore, the reduced oxidation of cortisol could inhibit the insulin signalling pathway via PTEN induction expression in the epithelial cells of endometrium, thus contributing to IR in women with PCOS [78]. Furthermore, as evidenced by elevated lipolysis and P53 activation in adipose tissue in an animal model of heart failure [98], the sympathetic nervous system (SNS) is also reported to be dysfunctional when coupled with IR. This implies that by promoting SNS dysfunction, IR fuels inflammation in PCOS [72]. Women with PCOS are more susceptible to several comorbidities, for instance MetS T2D, CVD, non-alcoholic fatty acid liver disease (NAFLD), and (EC) (Figure 1) [18]. IR plays a pivotal role in the pathogenesis of MetS [99], which is prevalent in 50% of women with PCOS [100]. Additionally, androgens also contribute significantly to the disease progression of MetS, with higher percentages being recorded in hyperandrogenic PCOS women (24.8%) compared to the non-hyperandrogenic counterparts. Strikingly, both waist circumference and free androgen index are independently correlated with MetS and IR [99]. Unfortunately, distinguishing the effects of obesity from MetS in women with PCOS is quite challenging [101]. IR is also a major mediator which further intensifies the risk of the metabolic disorders such as T2D and CVD [18] as it decreases nitric oxide (NO) and increases endothelin-1 (ET-1) in arterial endothelial cells. The increased synthesis of vasoconstrictors further impairs the vasodilation of insulin [102]. IR elevates the hepatic secretion of very-low-density lipoprotein (VLDL), eliminates VLDL and chylomicrons from circulation, and enhances the clearance of the high-density lipoprotein cholesterol (HDL-c) component, apolipoprotein A (apoA) [103]. Women with PCOS have predominant lipid abnormalities with a prevalence of 70% and higher concentrations of oxidised low-density lipoprotein cholesterol (LDL-c), increasing the risk of CVD. Studies revealed that lipoprotein A (24%) and apolipoprotein B (apoB) (14%) levels are elevated in PCOS patients [99,104,105]. Additionally, the decreased inhibition of lipolysis in adipose tissue, which results in an increased influx of FFAs into the liver and steatosis, is a function of IR [106], leading to NAFLD [107]. It has been speculated that hyperandrogenism impacts the expression of the LDL receptor (LDLR) in both adipocytes and liver, which is downregulated by 0.51-fold in women with PCOS [100,108]. Androgen excess in PCOS leads to the hypertrophy of adipocytes, and both are related to IR [55]. Moreover, inflammation is also associated with adipocyte hypertrophy, resulting in vascular compression, hypoxia, and increased inflammatory markers [55]. In ovaries, inflammation stimulates steroidogenic activity, theca cell proliferation, and the phosphorylation of the receptor, further increasing androgen excess and IR leading to the development of comorbidities such as T2D, atherosclerosis, and hypertension in women with PCOS [55]. The higher incidence of IR in women with PCOS also predisposes them to increased exposure of EC [109]. The increased expression of the insulin receptor along with the insulin-like growth factor 1 (IGF-1) receptor in endometrium leads to the crosstalk of their signalling pathways, contributing to the development of EC in women with PCOS [107,110].

5. Mitochondrial Dysregulation in the Pathophysiology of PCOS

Women with PCOS have compromised mitochondrial structures, content and dynamics in circulating leucocytes [111,112,113]. In addition to PCOS, altered mitochondrial morphology is also observed in other metabolic diseases, neurodegenerative disorders, and cancers [114,115]. ROS is the main pathogenesis factor in PCOS, as it is directly linked to mtDNA and OXPHOS efficiency (Figure 1). The marker levels of ROS in circulation, such as malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx), are heightened in women with PCOS, as the generated ROS overwhelms the antioxidant defence system. ROS also interferes with several cellular processes such as cell growth, differentiation, proliferation, and apoptosis [116]. As mtDNA is characterised as a biomarker for mitochondrial impairment, assessing its quantity serves as ideal objective in women with PCOS [24]. Lee et al. found a reduced mtDNA copy number in women with PCOS [117]. Similarly, in another study, women with PCOS and IR who also harboured mt-tRNA mutations were reported to have a lower number of mtDNA copies [118].
In the follicular fluids of PCOS patients, increased MDA levels, lowered total antioxidant capacity (TAC), and decreased thiol concentrations have also been reported. These results are also further reinforced by the analysis of ROS production in granulosa cells and leucocytes by Lai et al., where it was found that granulosa cells exhibited four times higher ROS compared to those of controls [90,119]. In another study, changes in the level of TCA and NAD catabolism in the follicular fluid, along with OS in cumulus cells (CCs), demonstrated a downregulated mitochondrial biogenesis rate, mtDNA, MMP, and PGC-1α gene expression and an upregulated PGC-1α promoter methylation rate in women with PCOS, compared to control group CCs [55]. Evidence of mitochondrial dysfunction in PCOS extends to broader reproductive biology, with the identification of 30 genes contributing to mitochondrial dysfunction signalling pathways in the granulosa cells of primordial follicles, including ATP5H, NDUFA2, PSEN2, and other apoptosis-regulating genes [120,121]. Furthermore, a metabolomics-based study of follicular fluid in PCOS patients revealed that mitochondrial dysfunction in granulosa cells, redox imbalance, and elevated OS levels may partly explain the metabolic disorders seen in PCOS [122].
Mitochondria could essentially be the target organelle that hampers the metabolic energy in obese PCOS patients who predominantly have IR. Severe OS can trigger obesity through the proliferation of preadipocyte followed by differentiation, thereby enlarging the mature adipocyte [123] and signalling hypothalamic neurons to increase hunger [55,124]. In addition, mitochondrial dysfunction and OS also contribute to inflammation and IR in PCOS. The formation of ROS by mononuclear cells has been linked to the aberrant development of pancreatic kb cell function, according to Malin et al. [125]. This is because ROS-induced OS triggers the activation of a nuclear protein that binds to DNA and promotes the transcription of TNF α [126]. According to observations, the creation of TNF diminishes the mtDNA-encoded cytochrome c oxidase 1 (COX-1) subunit, which lowers intracellular ATP synthesis and increases ROS accumulation, aggravating IR [121,127]. In a different study, myeloperoxidase (MPO), an enzyme released by WBC in inflammatory sites, and ROS production were assessed in PCOS-associated IR and non-insulin-resistant PCOS patients, with elevated levels being observed in women with PCOS-associated IR [55,128].
According to a further study, obese woman with PCOS and IR exhibited aberrant mitochondrial physiology in skeletal muscle, reduced phosphorylation efficiency, and elevated H2O2 emissions in contrast to insulin sensitive women [129]. Skov et al. studied the expression of OXPHOS genes in the skeletal muscle of women with PCOS and identified reduction in OXPHOS coupling efficiency in the obese (BMI > 33 kg/m2) women with elevated H2O2 emissions as compared to lean (BMI < 23 kg/m2) women [130]. These conditions bolster the compromised mitochondrial bioenergetics in obese women due to OS [55,129,130,131]. However, in skeletal muscle biopsies, no difference in mtDNA copy number was observed between the PCOS and control groups [132].
Moreover, several nuclear encoded OXPHOS genes, such as NDUFA3, SDHD, UCRC, COX7C, and ATP5H, were identified to be downregulated in women with PCOS [55]. NDUFA3 expression, which plays a role in follicular development and IR, is also associated with mtDNA copy number [133]. A further study observed that the SNPs in SDHD correlated with BMI, thus increasing obesity risk [134]. Meanwhile, the knockdown of COX7C, a gene inhibited during obesity, led to the accumulation of myocardial fat [55].
In another study, an induced pluripotent stem cell (iPSC) derived from the somatic cells of women with PCOS exhibited higher mtDNA copy numbers, biogenesis, and impaired respiration function, along with a higher expression of PGC1α, TFAM, and NRF-1 when compared to non-PCOS-derived iPSCs. The expressions of GLUT1 and GLUT3 were also decreased, indicating their roles in IR [55].

6. Variants Associated with IR in mtDNA Genes and Nuclear-Related mtDNA Genes in PCOS

Mitochondrial dysfunction can be a result of variants present in mtDNA genes or in nuclear-encoded mitochondrial genes (Table 1). The D-loop region is the most widely studied for mutational analysis in mtDNA, including deletions that impair mitochondrial functions while nuclear related genes are least studied [56,135]. Several frequent occurring D-loop variants were found in women of south-Indian ethnicity with PCOS [136]. In another study, many common to rare mtDNA variants in the D-loop region, as well as other mtDNA regions, were reported in women with PCOS in Indian and Chinese populations using next-generation sequencing (NGS) [136,137]. However, although these alterations were associated with mitochondrial dysfunction, their association with IR was not indicated in the reports.
While mitochondrial variants in PCOS have been extensively studied, there is limited research on variants specifically associated with insulin-resistant women with PCOS. These mtDNA mutations/variants may pose a risk for T2D in women with PCOS at later stages of their life. Different mtDNA alterations have been reported in PCOS-associated with IR, and all of these have strong functional implications regarding the stability and function of mitochondria (Table 1). The most conserved mitochondrial mutation, ND1 T3394C (p.Y30H), is linked with IR in women with PCOS [138,139]. The functional analysis of this mutation revealed that it affects the stability of ND1 subunit as well as the overall complex I assembly and its activity compromises MMP and ATP levels by increasing ROS production [56,140]. The ND2 C5178A corresponds to the substitution of leucine to methionine at the 237th amino acid position (p.M237L), which has been found to be associated with longevity [141] and acute myocardial infraction [141] and has also been reported to reduce ATP, MMP, and SOD activity and increase in ROS, MDA, and 8-hydroxydeoxyguanosine (8-OHDG), suggesting mitochondrial dysfunction [56,142]. Another mutation that was observed in PCOS patients with IR was tRNA Ser C7492T [143], which, along with homoplasmic ND5 T12338C (p.M1T), alters the highly conserved methionine by threonine shortening the chain by two amino acids [144]. The cybrid cell models further confirmed that T12338C decreased the stability of ND5 chain, thereby affecting the overall activity of respiratory complex [145]. Another mutation at ND5, T12811C (p.Y159H), impacted its transmembrane structure and function [146], suggesting a similar effect [56].
Furthermore, Ding et al. identified nine mt-tRNA-based mutations related to IR in women with PCOS, namely tRNALeu (UUR) C3275T, A3302G, tRNAGln T4363C, T4395C, tRNACys G5821A, tRNASer (UCN) C7492T, tRNAAsp A7543G, tRNALys A8343G, and tRNAGlu A14693G [118]. A homoplasmic tRNALys-based mutation found to be associated with IR in women with PCOS, A8343G has been reported to affect the adenine in TψC loop at the 54th position, impacting aminoacylation and binding affinity with mitochondrial elongation factor Tu, subsequently hampering the protein synthesis [56,147,148]. A sequencing analysis of a Chinese PCOS patient with IR identified a heteroplasmic tRNA Leu (UUR) A3302G mutation. This mutation occurred in the highly conserved region of the 5′ end of tRNALeu and impacted the stability of tRNA, as observed in cybrids, leading to severe complex I and IV deficiencies. This mutation also caused the abnormal processing of RNA19, an intermediate consisting of mitochondrial 16S rRNA, tRNALeu, and ND1 [149]. The mother and grandmother of this index case were diagnosed with T2D. In another family, a well conserved tRNALeu (UUR) C3275T-based mutation linked with IR in PCOS was reported. This mutation was also considered a risk factor for Leber’s hereditary optic neuropathy (LHON) and disrupted DNA base-paring (28A-46C), impairing the tRNA metabolism [56]. Saeed et al. analysed the mitochondrial tRNALeu (UUR) gene using Sanger sequencing (R = A or G), identifying ten mutations, with 80% located in the highly conserved region (3157–3275). These mutations (A > G and/or T > C) were predicted to disrupt secondary tRNA structure, affecting base pairing. Mutations that maintained base pairing were only observed in healthy controls. This highlights the role of tRNA mutations in the pathogenesis of IR associated with PCOS by impairing mitochondrial functions [150].
The analysis of mitochondrial D-loop identified variants, T152C, 523delAC, T16126C, and A16203G associated with increased or decreased IR in women with PCOS. Variants T16126C and A16203G were associated with IR (HOMA-IR > 4.86). In contrast, variants T152C and 523delAC were associated with non-IR (HOMA-IR ≤ 4.86) in women with PCOS [151].
Table 1. mtDNA and nuclear-related mitochondrial gene variants associated with IR in women with PCOS.
Table 1. mtDNA and nuclear-related mitochondrial gene variants associated with IR in women with PCOS.
GeneLocusMutationNucleotide Positions in tRNA/Protein ChangeTypeHomoplasmy/
Heteroplasmy
Associated DiseaseReference
tRNA GlumtDNAA14693G54MutationHomoplasmyDeafness, HTN MELAS,
LHON
[56,118,121]
tRNA LysmtDNAA8343G54MutationHomoplasmyMetS, PD risk factor, deafness[56,118,121,152]
tRNA Leu (UUR)mtDNAC3275T44MutationHomoplasmyMetS,
LHON
[56,118,121,152]
tRNA Leu (UUR)mtDNAA3302G71MutationHeteroplasmyMELAS, MM[56,118,121,152]
tRNA GlnmtDNAT4363C38MutationHomoplasmyHTN, MetS, possibly deafness, HTN, LHON[56,118,121,152]
tRNA GlnmtDNAT4395C6MutationHomoplasmyHTN[56,118,121,152]
tRNA ArgmtDNAT10454C55MutationHomoplasmyPossibly deafness, HTN[56,118,121,152]
tRNA AspmtDNAA7543G29MutationHeteroplasmyMEPR[56,118,121,152]
tRNA Ser (UCN)mtDNAC7492T26MutationHomoplasmyCPEO, HTN, deafness risk factor[56,118,121,152]
NC7mtDNA9-bp deletion DeletionHomoplasmy [16,56,152]
ND1mtDNAT3394CY30HMutation LHON,
diabetes
[56,152]
ND2mtDNAC5178AL237MMutation Acute MI,
Diabetes, atherosclerosis
[56]
ND5mtDNAT12338CM1TMutationHomoplasmyEH, LHON, MIDD[56,152]
ND5mtDNAT12811CY159HMutationHomoplasmyPossible LHON factor[56,152]
D-loopmtDNAT16126C SNP [137]
D-loopmtDNAA16203G SNP [137]
D-loopmtDNAT16217C SNP Endometriosis[151]
D-loopmtDNAA16316G SNP [151]
D-loopmtDNAA16203G SNP [151]
PGC-1αnDNArs8192678G482SSNP Risk factor for diabetes[55,135]
CPEO: chronic progressive external ophthalmoplegia; EH: endolymphatic hydrops; HTN: hypertension; LHON: Leber’s hereditary optic neuropathy; MetS: metabolic syndrome; MIDD: mitochondrial diabetes and deafness; MELAS: mitochondrial encephalomyopathy;, lactic acidosis, and stroke-like episodes; MEPR: mitochondrial encephalomyopathy, pyruvate dehydrogenase deficiency, and recurrent episodes; mtDNA: mitochondrial DNA; MM: mitochondrial myopathy; MI: myocardial infarction; nDNA: nuclear DNA; PD: Parkinson’s disease.
Women with PCOS are also shown to have deletions based on mtDNA. A deletion frequently observed in PCOS subjects in the variable region of the mitochondrial genome is a 9 bp sequence (CCCCCTCTA). This deletion ascended from the errors caused by DNA polymerase–gamma, which lack repair mechanisms. Intriguingly, Hu et al. identified that these deletions were predominantly linked with elevated serum glucose levels and lower insulin sensitivity indexes, advocating the contribution of IR in PCOS [16].
Recently, a study on PCOS patients investigated the impact of D-loop polymorphisms on the association of HOMA-IR and HOMA-β with BMI. Variant T16217C enhanced the association between BMI and HOMA-IR, highlighting the potential role of the variant in exacerbating IR in PCOS patients; in contrast, variant A16203G reduced the association between BMI and HOMA-β. Variant A16316G weakened the association between BMI and both HOMA-IR and HOMA-β simultaneously, suggesting a protective effect by mitigating the adverse impact of increased BMI on both IR and beta-cell function [151].
Moreover, a different study demonstrated the role of the PGC-1α gene in predisposing individuals to IR. PCOS patients exhibited significantly different allelic frequencies and genotypic distributions of PGC-1α Gly482Ser polymorphism, with carriers of the PGC-1α rs8192678 “Ser” allele, resulting in a predisposition to developing PCOS [55,135].

7. Therapeutic Interventions Targeting IR and Mitochondrial Dysfunction to Ameliorate PCOS

Various strategies, ranging from lifestyle modification to therapeutic drugs, have been found to be beneficial in ameliorating IR and mitochondrial function in PCOS. Future therapeutic strategies, such as mitochondrial transfer, are under study (Figure 2).

7.1. Exercise

Regular exercise is considered a primary treatment option and lifestyle change in women with PCOS [153]. Exercise is associated with enhanced cardiorespiratory fitness, decreased waist circumference, improvement in insulin sensitivity, and sex hormone levels such as FSH and testosterone [154,155,156]. A study by Dantas et al. reported that exercise elicits increased phosphorylation at the 308th threonine residue of AKT and AMPK, suggesting efficient GLUT4 translocation in the skeletal muscle of women with PCOS [157]. In another study [158], the upregulation of IR-associated genes such as PGC1α, peroxisome proliferator-activated receptor α (PPARα), nuclear factor of kappa light polypeptide gene enhancer in B-Cells inhibitor α (NFKBI α), and mitogen-activated protein kinase 3 (MAPK3) in the skeletal muscle of women with PCOS after a single bout of aerobic exercise [158] was observed. The international evidence-based guidelines for PCOS advise 150–300 min per week of moderate-intensity exercise or 75–150 min per week of vigorous-intensity exercise for the prevention of weight gain and the maintenance of health for women with PCOS [159]. A different study [160] indicated that high-intensity interval training (HIIT) may offer more favourable metabolic benefits, such as improvement in HOMA-IR and lower BMI, compared to lower intensity exercise for women with PCOS, as well as improving mitochondrial functions [36]. Recently, there has been increasing interest in ‘exerkines’, molecules that are released into circulation in response to exercise, transmitting the health impacts of physical activity. In the near future, bioengineered exerkines such as meterorin and irisin will serve as an ideal substitute for individuals incapable of exercise or those who exhibit the limited or non-existent expression of uncoupling protein (UCP1), such as PCOS patients [158].

7.2. Diet

Caloric restriction (CR) has proved to be the most efficacious and reproducible dietary intervention to increase healthy lifespan and ageing [161]. It is effective in improving insulin sensitivity [162,163] with over 40% with just 6 months of practice [164] by improving ß-cell function and reducing increased amounts of glucose and HbA1c [9]. It also ameliorates obesity and has also been reported to improve mitochondrial function by activating SIRT1 activator resveratrol that increases mitochondrial content, improving IR [25,165,166]. In recent years, there has been another more sustainable strategy than CR, known as time-restricted eating (TRE), which only limits the eating window without compromising on food consumption. TRE is reported to address mitochondrial dysfunction, IR and hyperandrogenaemia in women with PCOS. It is shown to upregulate genes linked to AMPK signalling, TCA cycle, and ETC [167]. Additionally, one month of maintaining a low-carbohydrate diet also elevated FSH and SHBG levels, thereby reducing IR, when compared to metformin [168]. Furthermore, the “dietary approaches to stop hypertension” (DASH) diet, containing minimal saturated fat, cholesterol, red and processed meats, and refined grains and sweets, but being rich in fruits, vegetables, whole grains, nuts, legumes, and fat-free/low-fat dairy [169], is reported to enhance insulin sensitivity and maintain glycemia, providing both long- and short-term benefits to women with PCOS [9]. In addition, low glycaemic index (GI)-based diets and high-fibre-based diets have also been reported to lower blood glucose and improve insulin sensitivity [170,171]; these results are supported by studies that dietary fibre consumption is conversely linked to fasting insulin, HOMA-IR, and the Matsuda insulin index [172,173]. Unfortunately, dietary changes often prove ineffective in the long term, mirroring the outcomes observed with anti-obesity medications. This may stem from the fact that female participants generally regain weight and struggle to maintain a normal BMI [168]. In recent years, another promising therapeutic target/biomarker for PCOS is advanced glycation end-products (AGEs). According to a one-year-long randomised controlled trial [174], a diet low in AGEs improves IR in obese patients with MetS, suggesting its plausibility in increasing insulin sensitivity and reducing hyperandrogenaemia and inflammation [78].

7.3. Therapeutic Agents

For adolescents diagnosed with PCOS, the first line of therapy has conventionally been combined hormonal contraceptives (CHCs), containing oestrogen (ethinyl oestradiol) and progestin. CHCs regulate menstrual cycles, resulting in predictable periods [175]. However, in women with PCOS with cardiovascular and metabolic risk factors, the excess oestrogenic components of CHCs worsen IR, although this effect is compensated by progestin [176]. In addition to CHCs, the growth hormone (GH) is another popular choice which is traditionally administrated to patients with infertility and disordered ovulation [177]. GH treatment lowers the oxidative stress index (OSI), the total oxidant status (TOS), and MMP and results in an over 50% reduction in apoptosis [178] by decreasing the levels of FOXO1, BAX, and caspases 3 and 9. It also diminishes mitochondrial dysfunction by increasing PI3K/AKT and BCL-2 [156].
Metformin, a drug targeting mitochondrial function is used as second-line treatment against PCOS along with ovarian laparoscopic surgery as is lowers the risk of ovarian hyperstimulation syndrome by stimulating exogenous gonadotropin [179,180]. In addition, it was found that metformin inhibits mitochondrial glycerophosphate dehydrogenase, a novel IR therapeutic target, suppressing gluconeogenesis [181]. Moreover, metformin administration in PCOS patients [178] results in decreased leptin levels, a hormone that regulates energy balance, and elevated adiponectin, a hormone that regulates glucose and fatty acid metabolism, providing synergistic activity [182]. This marks metformin as strong candidate for reducing the susceptibility to IR, T2D, and MetS in women with PCOS [107,156]. It has been observed that metformin reduces levels of proinflammatory cytokine IL-6 and CRP [156]. Although it delays the progression of glucose intolerance in women with PCOS, there is no impact on fasting glucose and lipids and other anthropometric parameters [107]. However, moderate weight loss has been observed in PCOS patients on metformin; it has been suggested that metformin be implemented on a long-term basis [183]. In comparison, GLP-1 receptor agonists such as exenatide and liraglutide result in modest weight loss women with PCOS by reducing inflammatory cytokines and improve sex hormone abnormalities, insulin sensitivity, and the menstrual cycle to even greater extent than metformin [184].
In addition to metformin, there are very few insulin-sensitizing drugs that have undergone clinical trials for use in women with PCOS. The ones that have are thiazolidinediones (TZDs), specifically pioglitazone and rosiglitazone, which enhance insulin sensitivity, reduce hyperandrogenaemia, and regulate the menstrual cycle in women with PCOS, acting through the activation of the peroxisome proliferator-activated receptor–gamma (PPARγ), a gene responsible for mitochondrial biogenesis. Furthermore, the administration of pioglitazone in metformin-resistant women with PCOS alleviates metabolic and hormonal abnormalities significantly, suggesting that a combination of drugs is more effective for the management of PCOS in women with more adverse phenotypes [107]. Several studies have also highlighted the role of myo-inositol (MYO) and D-chiro-inositol (DCI) as insulin sensitisers, improving metabolic and oxidative imbalances in women with PCOS [185,186]. Studies suggest that a MYO/DCI ratio of 40:1 is effective in treating women with PCOS, particularly when administered along with metformin or oral contraceptives, resulting in synergistic actions that mitigate severe effects. Moreover, MYO also acts as a secondary messenger in FSH signalling in the ovary, improving ovarian function. However, DCI supplementation could exacerbate insulin-mediated androgen production and fertility in women with PCOS [176,186]. Sodium glucose co-transporter type 2 inhibitor (SGLT2-i) and incretin mimetics are other insulin sensitisers with even stronger impacts on comorbidities such as obesity and CVD. SGLT2-i exhibits cardiovascular and nephron-protective effects by blocking glucose reuptake in the renal proximal tubule, leading to reduced arterial pressure and body weight [187]. Furthermore, SGLT2-i improves BMI and other anthropometric parameters in women with PCOS [188].
Besides insulin sensitisers, letrozole and anti-androgenic drugs have also shown effectiveness in improving IR in women with PCOS. Letrozole, an aromatase inhibitor, is a first-line pharmacological treatment for ovulation induction in infertile anovulatory women with PCOS [159]. A study found that combined letrozole and metformin treatment improved insulin sensitivity by lowering HOMA-IR, insulin levels, and lipid profiles in infertile women with PCOS, while also enhancing ovarian function [189]. Drugs, cyproterone acetate, spironolactone, finasteride, and flutamide are administered to treat hyperandrogenism [176] and IR in women with PCOS and/or hyperandrogenism [190].

7.4. Phytochemicals

There are several natural compounds applicable for the treatment of PCOS. For example, berberine, a plant alkaloid, improves insulin action in humans and rodents, by inhibiting the complex I of ETC and subsequent AMPK activation [25]. A decoction made from the roots of Polygonum multiflorum, known as Shouwu Jiangqi, has been found to modulate the insulin signalling pathway in rat models of PCOS [191]. Phytosterols in aloe vera can influence the steroidogenic response and induce the expression of oestrogen receptor protein, leading to a reduction in androgen levels and an increase in oestrogen levels, thereby alleviating PCOS symptoms. Moreover, aloe vera also has insulin sensitizing property effecting pancreatic beta cell function. The significant impact of cinnamon extract in improving insulin sensitivity was demonstrated by decreasing fasting blood sugar and IR in women with PCOS [192,193]. Silymarin, a flavonoid extracted from Silybum marianum L. Gaernt, also has anti-angiogenetic properties, enabling a reduction in follicular cell proliferation, thereby reducing testosterone levels and increasing SHBG protein synthesis and progesterone hormone levels in the corpus luteum. It also affects glucose 6-phosphate and inhibits gluconeogenesis and OS in women with PCOS [15].

7.5. Antioxidants

Vitamin D deficiency is associated with IR, infertility, altered SHBG and testosterone levels, and compromised lipid metabolism, factors which are also observed in PCOS; lower vitamin D levels exacerbate PCOS symptoms [10]. In a further study on a DHEA-induced PCOS rat model, vitamin D supplementation reduced obesity, body weight, and uterine and ovarian morphology [194]. Moreover, vitamin D has a positive influence on mitochondria as it upregulates the expression of TFAM and the mtDNA copy number, reduces ROS production, and strengthens MMP integrity [195,196]. Meanwhile, other natural antioxidants such as vitamin C and E are incapable of scavenging ROS as they are unable to bind to mitochondria. MitoQ10, a lipophilic cation, can easily pass through the phospholipid bilayer and mitochondrial membrane, then lodges at matrix surface, combating ROS and thus preventing OS and mitochondrial dysfunction. This is supported by a study on rats where PCOS-associated IR was treated with MitoQ10, resulting in an observed decrease in ROS levels, along with increases in MMP and ATP levels [197].
Another notable intervention involves increasing intracellular NAD+ levels, as insufficient NAD+ levels in the oocytes of women with PCOS may affect follicle/oocyte development. The supplementation of NAD+ using nicotinamide riboside (NR) is known to restore NAD+ levels and improve IR and mitochondrial functions in the GCs of PCOS women undergoing IVF treatment [198,199].

7.6. Mitochondrial Peptides

Mitochondrial peptides such as humanin, a mitochondrial open reading frame of 12S rRNA-c (MOTS-c), and small humanin-like proteins (SHLPs), which maintain mitochondrial function and viability [200], exhibit potential as novel therapeutic agents for PCOS. Humanin, discovered in 2001, is a 24-amino acid cytoprotective peptide [201] that can act as an antioxidant by restoring glutathione levels and enhancing mitobiogenesis [201]. It can also influence insulin secretion, thus enabling glucose uptake [202,203]. In a further study [204], PCOS-induced rats supplemented with the humanin analogue S14G (HNG) showed decreased fasting insulin and blood glucose levels, along with the upregulation of IRS1, AKT, and GLUT4, key proteins in insulin signalling. MOTS-c, a 16 amino acid peptide, increases AMPK and insulin sensitivity, while promoting NRF2 antioxidant genes. It also regulates mitochondrial insulin levels and homeostasis [205]. Moreover, SHLP-6, -2, and -3 also increase oxygen consumption rate by reducing apoptosis and ROS production [206,207].

7.7. Sleep and Mental Health Management

There are reports of association between depression and PCOS-related factors, such as hyperandrogenaemia, IR, and obesity, that warrant the exploration of potential therapies of PCOS-centred depression [208]. A proper sleeping schedule lowers the risk of CVD and other comorbidities linked with PCOS, suggesting is potential in reducing PCOS symptoms [168]. Melatonin, a hormone primarily secreted by the pineal gland and synthesised and metabolised in mitochondria, regulates the sleep cycle by reducing the time required to fall asleep, thereby improving sleep quality. It can also be combined with other therapeutic agents, such as insulin sensitisers and contraceptives, to reduce erratic sleep patterns, stabilise moods, improve insulin sensitivity, and decrease OS, ultimately enhancing the overall quality of life for women with PCOS [209]. Significant associations have been reported between the presence of OSA and fasting glucose or insulin resistance measured by HOMA-IR among women with PCOS, and potential underlying mechanisms include sympathetic overactivity, lipid metabolism alterations, oxidative stress and mitochondrial dysfunction, inflammation, and endothelial dysfunction, leading to diabetes and cardiovascular diseases in these women [210]. The dysregulated transcription of hypoxia after eight weeks of continuous positive airway pressure (CPAP) treatment for OSA in young and morbidly obese PCOS women improved metabolic and cardiovascular outcomes, resulting in modest improvements in insulin sensitivity after controlling for BMI, as well as reductions in the markers of sympathetic and diastolic blood pressure [210,211]. These beneficial effects increase with longer hours of CPAP use and have decreasing effects in women with PCOS with higher degrees of obesity [210]. Dysregulated hypoxia-inducible factor-1 (HIF-1) and HIF-2, members of the HIF family of transcriptional activators increase ROS, decrease antioxidant enzymes and mediate NOX2 gene activation; these are suggested to be molecular mechanisms underlying hypertension, T2D, and cognitive issues stemming from OSA-induced intermittent hypoxia [212].

7.8. Mitochondrial Transfer: Future Therapeutic Approach in IVF

Autologous mitochondrial transfer using ovarian stem cells or GCs, as well as the heterologous transfer of isolated mitochondria, represents a promising therapeutic strategy for infertile patients. The autologous approach has the advantage of avoiding heteroplasmy unlike in the heterologous approach. It has been demonstrated that transferring mitochondria isolated from GCs can improve embryo quality and increase pregnancy rate. Similarly, the transfer of mitochondria extracted from oogonial stem cells to mature oocytes has been shown to enhance the rate of high-quality embryos and successful embryo transfers, without altering the maternal mitochondrial genome in cases of recurrent IVF failure [213]. This method could also benefit women with IR who have compromised mitochondria. Additionally, recent research has highlighted the protective effects of mesenchymal stem cell (MSC) transplantation, possibly through the transfer of their own mitochondria, which improves ovarian mitochondrial function, redox status, and IR in a PCOS animal model [214]. These findings suggest that mitochondrial transfer could be a promising therapeutic approach for obese, insulin-resistant women with PCOS undergoing assisted reproductive technology (ART).

8. Conclusion and Future Perspectives

While numerous studies associate IR with PCOS and highlight the role of mitochondrial dysfunction in women with PCOS, a missing link connecting these components persists for understanding its role in the development of PCOS. This review aims to bridge the gap by synthesizing current empirical findings. Hyperandrogenism emerges as a crucial factor, driven by elevated LH levels that stimulate androgen secretion from ovarian theca cells. IR and hyperinsulinemia further exacerbate androgen production and impair insulin signalling and GLUT4 translocation, affecting glucose and lipid metabolism. Impaired lipid oxidation hampers mitochondrial function, generating OS and promoting ROS production, which reduces mtDNA copy number, a biomarker of mitochondrial dysfunction in PCOS. Furthermore, IR also predisposes women to comorbidities like T2D and other metabolic complications. The relationship between these factors is not linear but an intricate network forming a vicious cycle. Although more studies are needed in IR and women with PCOS for confirmation, therapeutic interventions targeting multiple key points may more effectively mitigate metabolic complications in PCOS. Exercise, diet, antioxidants and CHCs remain primary defences, but novel interventions such as mitochondrial peptides, AGE-based diets, and antioxidants like MitoQ10 are being explored. Furthermore, clinical trials using mitochondria transfer techniques are required to improve ART outcome in PCOS patients who are obese/insulin resistant. Understanding the interplay between IR, PCOS, and mitochondrial dysfunction can lead to more holistic management strategies for PCOS and related comorbidities.

Author Contributions

S.P.T. complied the articles and wrote the manuscript. P.S. conceive the idea, supervised, edited, and approved the final version of the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

The work is supported by grants from Indian Council of Medical Research (ICMR) (IIRP-2023-0000049). The authors also acknowledge the necessary support from ICMR-National Institute for Research in Reproductive and Child Health (NIRRCH) (REV/1872/05-2025).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The authors acknowledge Biorender.com for preparation of manuscript figure.

Conflicts of Interest

The authors declare no competing or financial interests.

Abbreviations

The following abbreviations are used in this manuscript:
PCOSPolycystic Ovary Syndrome
IRInsulin Resistance
T2DType 2 Diabetes
CVDCardiovascular Disease
ECEndometrial Cancer
LHLuteinizing Hormone
FSHFollicle-Stimulating Hormone
SHBGSex Hormone-Binding Globulin
ROSReactive Oxygen Species
OSOxidative Stress
mtDNAMitochondrial DNA
ETCElectron Transport Chain
OXPHOSOxidative Phosphorylation
PGC-1αPeroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
NRF-1Nuclear Respiratory Factor 1
NRF-2Nuclear Respiratory Factor 2
ERR-αOestrogen-Related Receptor Alpha
TFAMTranscription Factor A, Mitochondrial
Mfn1/2Mitofusin 1/Mitofusin 2
Opa1Optic Atrophy 1
DRP1Dynamin-Related Protein 1
Fis1Mitochondrial Fission 1 Protein
DAGDiacylglycerol
CERCeramide
PKCProtein Kinase C
AKTProtein Kinase B
IRS1Insulin Receptor Substrate 1
GLUT4Glucose Transporter Type 4
FFAsFree Fatty Acids
PAPalmitate
AIFApoptosis-Inducing Factor
NOX4NADPH Oxidase 4
MCP-1Monocyte Chemoattractant Protein-1
PTP1BProtein Tyrosine Phosphatase 1B
JNKc-Jun N-terminal Kinase
NF-κBNuclear Factor Kappa B
MAPKMitogen-Activated Protein Kinase
FOXO1Forkhead Box Protein O1
HMOX1Heme Oxygenase 1
NOX2NADPH Oxidase 2
RAC1Ras-Related C3 Botulinum Toxin Substrate 1
P47PHOX47 kDa Subunit of NADPH Oxidase
CaMKIICalcium/Calmodulin-Dependent Protein Kinase II
Myo1cMyosin-1c
MAMsMitochondria-Associated ER Membranes
mTORMammalian Target of Rapamycin
AMPKAMP-Activated Protein Kinase
SIRT1Sirtuin 1
DNMT1DNA Methyltransferase 1
PSEN2 Presenilin 2
COX-1Cytochrome c Oxidase Subunit 1
MPOMyeloperoxidase
SDHD Succinate Dehydrogenase Complex Subunit D
UCRCUbiquinol–Cytochrome c Reductase Core Protein
COX7CCytochrome c Oxidase Subunit 7C
GLUT1Glucose Transporter Type 1
GLUT3Glucose Transporter Type 3
iPSCInduced Pluripotent Stem Cell
ND1NADH Dehydrogenase 1
ND2NADH Dehydrogenase 2
8-OHDG8-Hydroxy-2′-Deoxyguanosine
ND5NADH Dehydrogenase 5
LHONLeber’s Hereditary Optic Neuropathy
TFAMTranscription Factor A, Mitochondrial
NRF-1Nuclear Respiratory Factor 1
PPARαPeroxisome Proliferator-Activated Receptor Alpha
NFKBI αNuclear Factor of Kappa Light Polypeptide Gene Enhancer in B-Cells Inhibitor Alpha
MAPK3Mitogen-Activated Protein Kinase 3
SIRT1Sirtuin 1
GLUT4Glucose Transporter Type 4
HNGHumanin Analogue S14G
TOSTotal Oxidant Status
BCL-2B-Cell Lymphoma 2
SGLT2-iSodium-Glucose Cotransporter 2 Inhibitor
MYOMyo-Inositol
DCID-Chiro-Inositol
MOTS-cMitochondrial Open Reading Frame of 12S rRNA-c
SHLPSmall Humanin-Like Protein
ARTAssisted Reproductive Technology
MSCMesenchymal Stem Cell
NRNicotinamide Riboside
SHBGSex Hormone-Binding Globulin
OSAObstructive Sleep Apnoea

References

  1. Barry, J.A.; Azizia, M.M.; Hardiman, P.J. Risk of Endometrial, Ovarian and Breast Cancer in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis. Hum. Reprod. Update 2014, 20, 748–758. [Google Scholar] [CrossRef] [PubMed]
  2. Gunning, M.N.; Petermann, T.S.; Crisosto, N.; Van Rijn, B.B.; De Wilde, M.A.; Christ, J.P.; Uiterwaal, C.S.P.M.; De Jager, W.; Eijkemans, M.J.C.; Kunselman, A.R.; et al. Cardiometabolic Health in Offspring of Women with PCOS Compared to Healthy Controls: A Systematic Review and Individual Participant Data Meta-Analysis. Hum. Reprod. Update 2020, 26, 104–118. [Google Scholar] [CrossRef]
  3. Kakoly, N.S.; Earnest, A.; Teede, H.J.; Moran, L.J.; Joham, A.E. The Impact of Obesity on the Incidence of Type 2 Diabetes Among Women with Polycystic Ovary Syndrome. Diabetes Care 2019, 42, 560–567. [Google Scholar] [CrossRef] [PubMed]
  4. Dumesic, D.A.; Oberfield, S.E.; Stener-Victorin, E.; Marshall, J.C.; Laven, J.S.; Legro, R.S. Scientific Statement on the Diagnostic Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary Syndrome. Endocr. Rev. 2015, 36, 487–525. [Google Scholar] [CrossRef]
  5. Reaven, G.M. The Metabolic Syndrome: Requiescat in Pace. Clin. Chem. 2005, 51, 931–938. [Google Scholar] [CrossRef] [PubMed]
  6. Ng, M.; Fleming, T.; Robinson, M.; Thomson, B.; Graetz, N.; Margono, C.; Mullany, E.C.; Biryukov, S.; Abbafati, C.; Abera, S.F.; et al. Global, Regional, and National Prevalence of Overweight and Obesity in Children and Adults during 1980–2013: A Systematic Analysis for the Global Burden of Disease Study 2013. Lancet 2014, 384, 766–781. [Google Scholar] [CrossRef]
  7. Brower, M.A.; Hai, Y.; Jones, M.R.; Guo, X.; Chen, Y.D.I.; Rotter, J.I.; Krauss, R.M.; Legro, R.S.; Azziz, R.; Goodarzi, M.O. Bidirectional Mendelian Randomization to Explore the Causal Relationships between Body Mass Index and Polycystic Ovary Syndrome. Hum. Reprod. 2019, 34, 127–136. [Google Scholar] [CrossRef]
  8. Zhu, S.; Zhang, B.; Jiang, X.; Li, Z.; Zhao, S.; Cui, L.; Chen, Z.J. Metabolic Disturbances in Non-Obese Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis. Fertil. Steril. 2019, 111, 168–177. [Google Scholar] [CrossRef]
  9. Shang, Y.; Zhou, H.; Hu, M.; Feng, H. Effect of Diet on Insulin Resistance in Polycystic Ovary Syndrome. J. Clin. Endocrinol. Metab. 2020, 105, 3346–3360. [Google Scholar] [CrossRef]
  10. Morgante, G.; Darino, I.; Spanò, A.; Luisi, S.; Luddi, A.; Piomboni, P.; Governini, L.; De Leo, V. PCOS Physiopathology and Vitamin D Deficiency: Biological Insights and Perspectives for Treatment. J. Clin. Med. 2022, 11, 4509. [Google Scholar] [CrossRef]
  11. Marx, T.L.; Mehta, A.E. Polycystic Ovary Syndrome: Pathogenesis and Treatment over the Short and Long Term. Cleve Clin. J. Med. 2003, 70, 31–45. [Google Scholar] [CrossRef] [PubMed]
  12. Goodarzi, M.O.; Carmina, E.; Azziz, R. DHEA, DHEAS and PCOS. J. Steroid Biochem. Mol. Biol. 2015, 145, 213–225. [Google Scholar] [CrossRef] [PubMed]
  13. Deswal, R.; Yadav, A.; Dang, A.S. Sex Hormone Binding Globulin—An Important Biomarker for Predicting PCOS Risk: A Systematic Review and Meta-Analysis. Syst. Biol. Reprod. Med. 2018, 64, 12–24. [Google Scholar] [CrossRef] [PubMed]
  14. Hopkinson, Z.E.C.; Sattar, N.; Fleming, R.; Greer, I.A. Polycystic Ovarian Syndrome: The Metabolic Syndrome Comes to Gynaecology. BMJ 1998, 317, 329–332. [Google Scholar] [CrossRef]
  15. Ashkar, F.; Rezaei, S.; Salahshoornezhad, S.; Vahid, F.; Gholamalizadeh, M.; Dahka, S.M.; Doaei, S. The Role of Medicinal Herbs in Treatment of Insulin Resistance in Patients with Polycystic Ovary Syndrome: A Literature Review. Biomol. Concepts 2020, 11, 57–75. [Google Scholar] [CrossRef]
  16. Moosa, A.; Ghani, M.; O’Neill, H.C. Genetic Associations with Polycystic Ovary Syndrome: The Role of the Mitochondrial Genome; a Systematic Review and Meta-Analysis. J. Clin. Pathol. 2022, 75, 815–824. [Google Scholar] [CrossRef]
  17. Mansouri, A.; Gattolliat, C.H.; Asselah, T. Mitochondrial Dysfunction and Signaling in Chronic Liver Diseases. Gastroenterology 2018, 155, 629–647. [Google Scholar] [CrossRef]
  18. Shukla, P.; Mukherjee, S. Mitochondrial Dysfunction: An Emerging Link in the Pathophysiology of Polycystic Ovary Syndrome. Mitochondrion 2020, 52, 24–39. [Google Scholar] [CrossRef]
  19. Cook, K.L.; Soto-Pantoja, D.R.; Clarke, P.A.G.; Cruz, M.I.; Zwart, A.; Wärri, A.; Hilakivi-Clarke, L.; Roberts, D.D.; Clarke, R. Endoplasmic Reticulum Stress Protein GRP78 Modulates Lipid Metabolism to Control Drug Sensitivity and Antitumor Immunity in Breast Cancer. Cancer Res. 2016, 76, 5657–5670. [Google Scholar] [CrossRef]
  20. Tuppen, H.A.L.; Blakely, E.L.; Turnbull, D.M.; Taylor, R.W. Mitochondrial DNA Mutations and Human Disease. Biochim. Biophys. Acta 2010, 1797, 113–128. [Google Scholar] [CrossRef]
  21. Schon, E.A.; Dimauro, S.; Hirano, M. Human Mitochondrial DNA: Roles of Inherited and Somatic Mutations. Nat. Rev. Genet. 2012, 13, 878–890. [Google Scholar] [CrossRef] [PubMed]
  22. Sharma, H.; Singh, A.; Sharma, C.; Jain, S.K.; Singh, N. Mutations in the Mitochondrial DNA D-Loop Region Are Frequent in Cervical Cancer. Cancer Cell Int. 2005, 5, 34. [Google Scholar] [CrossRef] [PubMed]
  23. Popov, L.D. Mitochondrial Biogenesis: An Update. J. Cell Mol. Med. 2020, 24, 4892–4899. [Google Scholar] [CrossRef] [PubMed]
  24. Siemers, K.M.; Klein, A.K.; Baack, M.L. Mitochondrial Dysfunction in PCOS: Insights into Reproductive Organ Pathophysiology. Int. J. Mol. Sci. 2023, 24, 13123. [Google Scholar] [CrossRef]
  25. Montgomery, M.K.; Turner, N. Mitochondrial Dysfunction and Insulin Resistance: An Update. Endocr. Connect. 2015, 4, R1–R15. [Google Scholar] [CrossRef]
  26. Westermann, B. Mitochondrial Fusion and Fission in Cell Life and Death. Nat. Rev. Mol. Cell Biol. 2010, 11, 872–884. [Google Scholar] [CrossRef]
  27. Twig, G.; Hyde, B.; Shirihai, O.S. Mitochondrial Fusion, Fission and Autophagy as a Quality Control Axis: The Bioenergetic View. Biochim. Biophys. Acta 2008, 1777, 1092–1097. [Google Scholar] [CrossRef]
  28. Cipolat, S.; De Brito, O.M.; Dal Zilio, B.; Scorrano, L. OPA1 Requires Mitofusin 1 to Promote Mitochondrial Fusion. Proc. Natl. Acad. Sci. USA 2004, 101, 15927–15932. [Google Scholar] [CrossRef]
  29. Hales, K.G.; Fuller, M.T. Developmentally Regulated Mitochondrial Fusion Mediated by a Conserved, Novel, Predicted GTPase. Cell 1997, 90, 121–129. [Google Scholar] [CrossRef]
  30. Hales, K.G. The Machinery of Mitochondrial Fusion, Division, and Distribution, and Emerging Connections to Apoptosis. Mitochondrion 2004, 4, 285–308. [Google Scholar] [CrossRef]
  31. Martin, S.D.; McGee, S.L. The Role of Mitochondria in the Aetiology of Insulin Resistance and Type 2 Diabetes. Biochim. Biophys. Acta 2014, 1840, 1303–1312. [Google Scholar] [CrossRef] [PubMed]
  32. Westermeier, F.; Navarro-Marquez, M.; López-Crisosto, C.; Bravo-Sagua, R.; Quiroga, C.; Bustamante, M.; Verdejo, H.E.; Zalaquett, R.; Ibacache, M.; Parra, V.; et al. Defective Insulin Signaling and Mitochondrial Dynamics in Diabetic Cardiomyopathy. Biochim. Biophys. Acta 2015, 1853, 1113–1118. [Google Scholar] [CrossRef]
  33. Yaribeygi, H.; Farrokhi, F.R.; Butler, A.E.; Sahebkar, A. Insulin Resistance: Review of the Underlying Molecular Mechanisms. J. Cell Physiol. 2019, 234, 8152–8161. [Google Scholar] [CrossRef]
  34. Schmitz-Peiffer, C.; Craig, D.L.; Biden, T.J. Ceramide Generation Is Sufficient to Account for the Inhibition of the Insulin-Stimulated PKB Pathway in C2C12 Skeletal Muscle Cells Pretreated with Palmitate. J. Biol. Chem. 1999, 274, 24202–24210. [Google Scholar] [CrossRef] [PubMed]
  35. Fan, P.; Xie, X.H.; Chen, C.H.; Peng, X.; Zhang, P.; Yang, C.; Wang, Y.T. Molecular Regulation Mechanisms and Interactions Between Reactive Oxygen Species and Mitophagy. DNA Cell Biol. 2019, 38, 10–22. [Google Scholar] [CrossRef] [PubMed]
  36. Malamouli, M.; Levinger, I.; McAinch, A.J.; Trewin, A.J.; Rodgers, R.J.; Moreno-Asso, A. The Mitochondrial Profile in Women with Polycystic Ovary Syndrome: Impact of Exercise. J. Mol. Endocrinol. 2022, 68, R11–R23. [Google Scholar] [CrossRef]
  37. Samuel, V.T.; Petersen, K.F.; Shulman, G.I. Lipid-Induced Insulin Resistance: Unravelling the Mechanism. Lancet 2010, 375, 2267–2277. [Google Scholar] [CrossRef]
  38. Turner, N.; Kowalski, G.M.; Leslie, S.J.; Risis, S.; Yang, C.; Lee-Young, R.S.; Babb, J.R.; Meikle, P.J.; Lancaster, G.I.; Henstridge, D.C.; et al. Distinct Patterns of Tissue-Specific Lipid Accumulation during the Induction of Insulin Resistance in Mice by High-Fat Feeding. Diabetologia 2013, 56, 1638–1648. [Google Scholar] [CrossRef]
  39. Morino, K.; Petersen, K.F.; Dufour, S.; Befroy, D.; Frattini, J.; Shatzkes, N.; Neschen, S.; White, M.F.; Bilz, S.; Sono, S.; et al. Reduced Mitochondrial Density and Increased IRS-1 Serine Phosphorylation in Muscle of Insulin-Resistant Offspring of Type 2 Diabetic Parents. J. Clin. Investig. 2005, 115, 3587–3593. [Google Scholar] [CrossRef]
  40. Lepretti, M.; Martucciello, S.; Aceves, M.A.B.; Putti, R.; Lionetti, L. Omega-3 Fatty Acids and Insulin Resistance: Focus on the Regulation of Mitochondria and Endoplasmic Reticulum Stress. Nutrients 2018, 10, 350. [Google Scholar] [CrossRef]
  41. Sethi, J.K.; Vidal-Puig, A.J. Thematic Review Series: Adipocyte Biology. Adipose Tissue Function and Plasticity Orchestrate Nutritional Adaptation. J. Lipid Res. 2007, 48, 1253–1262. [Google Scholar] [CrossRef] [PubMed]
  42. Lowell, B.B.; Shulman, G.I. Mitochondrial Dysfunction and Type 2 Diabetes. Science 2005, 307, 384–387. [Google Scholar] [CrossRef] [PubMed]
  43. Di Meo, S.; Iossa, S.; Venditti, P. Skeletal Muscle Insulin Resistance: Role of Mitochondria and Other ROS Sources. J. Endocrinol. 2017, 233, R15–R42. [Google Scholar] [CrossRef]
  44. Mancini, G.; Pirruccio, K.; Yang, X.; Blücher, M.; Rodeheffer, M.; Horvath, T.L. Mitofusin 2 in Mature Adipocytes Controls Adiposity and Body Weight. Cell Rep. 2019, 26, 2849–2858.e4. [Google Scholar] [CrossRef] [PubMed]
  45. Cortés-Rojo, C.; Vargas-Vargas, M.A.; Olmos-Orizaba, B.E.; Rodríguez-Orozco, A.R.; Calderón-Cortés, E. Interplay between NADH Oxidation by Complex I, Glutathione Redox State and Sirtuin-3, and Its Role in the Development of Insulin Resistance. Biochim. Biophys. Acta Mol. Basis Dis. 2020, 1866, 165801. [Google Scholar] [CrossRef]
  46. Ahmed, B.; Sultana, R.; Greene, M.W. Adipose Tissue and Insulin Resistance in Obese. Biomed. Pharmacother. 2021, 137, 111315. [Google Scholar] [CrossRef]
  47. Joza, N.; Pospisilik, J.A.; Hangen, E.; Hanada, T.; Modjtahedi, N.; Penninger, J.M.; Kroemer, G. AIF: Not Just an Apoptosis-Inducing Factor. Ann. N. Y. Acad. Sci. 2009, 1171, 2–11. [Google Scholar] [CrossRef]
  48. Pospisilik, J.A.; Knauf, C.; Joza, N.; Benit, P.; Orthofer, M.; Cani, P.D.; Ebersberger, I.; Nakashima, T.; Sarao, R.; Neely, G.; et al. Targeted Deletion of AIF Decreases Mitochondrial Oxidative Phosphorylation and Protects from Obesity and Diabetes. Cell 2007, 131, 476–491. [Google Scholar] [CrossRef]
  49. Bruce, C.R.; Hoy, A.J.; Turner, N.; Watt, M.J.; Allen, T.L.; Carpenter, K.; Cooney, G.J.; Febbraio, M.A.; Kraegen, E.W. Overexpression of Carnitine Palmitoyltransferase-1 in Skeletal Muscle Is Sufficient to Enhance Fatty Acid Oxidation and Improve High-Fat Diet-Induced Insulin Resistance. Diabetes 2009, 58, 550–558. [Google Scholar] [CrossRef]
  50. Han, C.Y.; Umemoto, T.; Omer, M.; Den Hartigh, L.J.; Chiba, T.; LeBoeuf, R.; Buller, C.L.; Sweet, I.R.; Pennathur, S.; Abel, E.D.; et al. NADPH Oxidase-Derived Reactive Oxygen Species Increases Expression of Monocyte Chemotactic Factor Genes in Cultured Adipocytes. J. Biol. Chem. 2012, 287, 10379–10393. [Google Scholar] [CrossRef]
  51. Furukawa, S.; Fujita, T.; Shimabukuro, M.; Iwaki, M.; Yamada, Y.; Nakajima, Y.; Nakayama, O.; Makishima, M.; Matsuda, M.; Shimomura, I. Increased Oxidative Stress in Obesity and Its Impact on Metabolic Syndrome. J. Clin. Investig. 2004, 114, 1752–1761. [Google Scholar] [CrossRef] [PubMed]
  52. Den Hartigh, L.J.; Omer, M.; Goodspeed, L.; Wang, S.; Wietecha, T.; O’Brien, K.D.; Han, C.Y. Adipocyte-Specific Deficiency of NADPH Oxidase 4 Delays the Onset of Insulin Resistance and Attenuates Adipose Tissue Inflammation in Obesity. Arterioscler. Thromb. Vasc. Biol. 2017, 37, 466–475. [Google Scholar] [CrossRef] [PubMed]
  53. Mahadev, K.; Motoshima, H.; Wu, X.; Ruddy, J.M.; Arnold, R.S.; Cheng, G.; Lambeth, J.D.; Goldstein, B.J. The NAD(P)H Oxidase Homolog Nox4 Modulates Insulin-Stimulated Generation of H2O2 and Plays an Integral Role in Insulin Signal Transduction. Mol. Cell Biol. 2004, 24, 1844–1854. [Google Scholar] [CrossRef] [PubMed]
  54. Roos, G.; Messens, J. Protein Sulfenic Acid Formation: From Cellular Damage to Redox Regulation. Free Radic. Biol. Med. 2011, 51, 314–326. [Google Scholar] [CrossRef]
  55. Zhang, J.; Bao, Y.; Zhou, X.; Zheng, L. Polycystic Ovary Syndrome and Mitochondrial Dysfunction. Reprod. Biol. Endocrinol. 2019, 17, 67. [Google Scholar] [CrossRef]
  56. Dong, X.C.; Liu, C.; Zhuo, G.C.; Ding, Y. Potential Roles of MtDNA Mutations in PCOS-IR: A Review. Diabetes Metab. Syndr. Obes. 2023, 16, 139–149. [Google Scholar] [CrossRef]
  57. Cheng, Z.; Tseng, Y.; White, M.F. Insulin Signaling Meets Mitochondria in Metabolism. Trends Endocrinol. Metab. 2010, 21, 589–598. [Google Scholar] [CrossRef]
  58. Balteau, M.; Tajeddine, N.; De Meester, C.; Ginion, A.; Des Rosiers, C.; Brady, N.R.; Sommereyns, C.; Horman, S.; Vanoverschelde, J.L.; Gailly, P.; et al. NADPH Oxidase Activation by Hyperglycaemia in Cardiomyocytes Is Independent of Glucose Metabolism but Requires SGLT1. Cardiovasc. Res. 2011, 92, 237–246. [Google Scholar] [CrossRef]
  59. Yip, M.F.; Ramm, G.; Larance, M.; Hoehn, K.L.; Wagner, M.C.; Guilhaus, M.; James, D.E. CaMKII-Mediated Phosphorylation of the Myosin Motor Myo1c Is Required for Insulin-Stimulated GLUT4 Translocation in Adipocytes. Cell Metab. 2008, 8, 384–398. [Google Scholar] [CrossRef]
  60. Townsend, L.K.; Medak, K.D.; Peppler, W.T.; Meers, G.M.; Scott Rector, R.; LeBlanc, P.J.; Wright, D.C. High-Saturated-Fat Diet-Induced Obesity Causes Hepatic Interleukin-6 Resistance via Endoplasmic Reticulum Stress. J. Lipid Res. 2019, 60, 1236–1249. [Google Scholar] [CrossRef]
  61. Tubbs, E.; Theurey, P.; Vial, G.; Bendridi, N.; Bravard, A.; Chauvin, M.A.; Ji-Cao, J.; Zoulim, F.; Bartosch, B.; Ovize, M.; et al. Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Integrity Is Required for Insulin Signaling and Is Implicated in Hepatic Insulin Resistance. Diabetes 2014, 63, 3279–3294. [Google Scholar] [CrossRef] [PubMed]
  62. Rieusset, J.; Fauconnier, J.; Paillard, M.; Belaidi, E.; Tubbs, E.; Chauvin, M.A.; Durand, A.; Bravard, A.; Teixeira, G.; Bartosch, B.; et al. Disruption of Calcium Transfer from ER to Mitochondria Links Alterations of Mitochondria-Associated ER Membrane Integrity to Hepatic Insulin Resistance. Diabetologia 2016, 59, 614–623. [Google Scholar] [CrossRef] [PubMed]
  63. Townsend, L.K.; Brunetta, H.S.; Mori, M.A.S. Mitochondria-Associated ER Membranes in Glucose Homeostasis and Insulin Resistance. Am. J. Physiol. Endocrinol. Metab. 2020, 319, E1053–E1060. [Google Scholar] [CrossRef]
  64. Ye, J. Mechanism of Insulin Resistance in Obesity: A Role of ATP. Front. Med. 2021, 15, 372–382. [Google Scholar] [CrossRef] [PubMed]
  65. Yin, L.; Luo, M.; Wang, R.; Ye, J.; Wang, X. Mitochondria in Sex Hormone-Induced Disorder of Energy Metabolism in Males and Females. Front. Endocrinol. 2021, 12, 749451. [Google Scholar] [CrossRef]
  66. Patti, M.E.; Butte, A.J.; Crunkhorn, S.; Cusi, K.; Berria, R.; Kashyap, S.; Miyazaki, Y.; Kohane, I.; Costello, M.; Saccone, R.; et al. Coordinated Reduction of Genes of Oxidative Metabolism in Humans with Insulin Resistance and Diabetes: Potential Role of PGC1 and NRF1. Proc. Natl. Acad. Sci. USA 2003, 100, 8466–8471. [Google Scholar] [CrossRef]
  67. Puigserver, P.; Spiegelman, B.M. Peroxisome Proliferator-Activated Receptor-Gamma Coactivator 1 Alpha (PGC-1 Alpha): Transcriptional Coactivator and Metabolic Regulator. Endocr. Rev. 2003, 24, 78–90. [Google Scholar] [CrossRef]
  68. Vondra, K.; Rath, R.; Bass, A.; Slabochová, Z.; Teisinger, J.; Vítek, V. Enzyme Activities in Quadriceps Femoris Muscle of Obese Diabetic Male Patients. Diabetologia 1977, 13, 527–529. [Google Scholar] [CrossRef]
  69. Yazıcı, D.; Sezer, H. Insulin Resistance, Obesity and Lipotoxicity. Adv. Exp. Med. Biol. 2017, 960, 277–304. [Google Scholar] [CrossRef]
  70. Shock, L.S.; Thakkar, P.V.; Peterson, E.J.; Moran, R.G.; Taylor, S.M. DNA Methyltransferase 1, Cytosine Methylation, and Cytosine Hydroxymethylation in Mammalian Mitochondria. Proc. Natl. Acad. Sci. USA 2011, 108, 3630–3635. [Google Scholar] [CrossRef]
  71. Cheng, Z.; Guo, S.; Copps, K.; Dong, X.; Kollipara, R.; Rodgers, J.T.; Depinho, R.A.; Puigserver, P.; White, M.F. Foxo1 Integrates Insulin Signaling with Mitochondrial Function in the Liver. Nat. Med. 2009, 15, 1307–1311. [Google Scholar] [CrossRef] [PubMed]
  72. De Kreutzenberg, S.V.; Ceolotto, G.; Papparella, I.; Bortoluzzi, A.; Semplicini, A.; Dalla Man, C.; Cobelli, C.; Fadini, G.P.; Avogaro, A. Downregulation of the Longevity-Associated Protein Sirtuin 1 in Insulin Resistance and Metabolic Syndrome: Potential Biochemical Mechanisms. Diabetes 2010, 59, 1006–1015. [Google Scholar] [CrossRef]
  73. O’Hagan, H.M.; Wang, W.; Sen, S.; DeStefano Shields, C.; Lee, S.S.; Zhang, Y.W.; Clements, E.G.; Cai, Y.; Van Neste, L.; Easwaran, H.; et al. Oxidative Damage Targets Complexes Containing DNA Methyltransferases, SIRT1, and Polycomb Members to Promoter CpG Islands. Cancer Cell 2011, 20, 606–619. [Google Scholar] [CrossRef] [PubMed]
  74. O’Hagan, H.M.; Mohammad, H.P.; Baylin, S.B. Double Strand Breaks Can Initiate Gene Silencing and SIRT1-Dependent Onset of DNA Methylation in an Exogenous Promoter CpG Island. PLoS Genet. 2008, 4, e1000155. [Google Scholar] [CrossRef]
  75. Peng, L.; Yuan, Z.; Ling, H.; Fukasawa, K.; Robertson, K.; Olashaw, N.; Koomen, J.; Chen, J.; Lane, W.S.; Seto, E. SIRT1 Deacetylates the DNA Methyltransferase 1 (DNMT1) Protein and Alters Its Activities. Mol. Cell Biol. 2011, 31, 4720–4734. [Google Scholar] [CrossRef]
  76. Zheng, L.D.; Linarelli, L.E.; Liu, L.; Wall, S.S.; Greenawald, M.H.; Seidel, R.W.; Estabrooks, P.A.; Almeida, F.A.; Cheng, Z. Insulin Resistance Is Associated with Epigenetic and Genetic Regulation of Mitochondrial DNA in Obese Humans. Clin. Epigenetics 2015, 7, 1–9. [Google Scholar] [CrossRef] [PubMed]
  77. Dumesic, D.A.; Akopians, A.L.; Madrigal, V.K.; Ramirez, E.; Margolis, D.J.; Sarma, M.K.; Thomas, A.M.; Grogan, T.R.; Haykal, R.; Schooler, T.A.; et al. Hyperandrogenism Accompanies Increased Intra-Abdominal Fat Storage in Normal Weight Polycystic Ovary Syndrome Women. J. Clin. Endocrinol. Metab. 2016, 101, 4178–4188. [Google Scholar] [CrossRef]
  78. Jiang, N.X.; Li, X.L. The Disorders of Endometrial Receptivity in PCOS and Its Mechanisms. Reprod. Sci. 2022, 29, 2465–2476. [Google Scholar] [CrossRef]
  79. Rosenfield, R.L.; Ehrmann, D.A. The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited. Endocr. Rev. 2016, 37, 467–520. [Google Scholar] [CrossRef]
  80. Baillargeon, J.P.; Carpentier, A. Role of Insulin in the Hyperandrogenemia of Lean Women with Polycystic Ovary Syndrome and Normal Insulin Sensitivity. Fertil. Steril. 2007, 88, 886–893. [Google Scholar] [CrossRef]
  81. Baillargeon, J.P.; Nestler, J.E. Commentary: Polycystic Ovary Syndrome: A Syndrome of Ovarian Hypersensitivity to Insulin? J. Clin. Endocrinol. Metab. 2006, 91, 22–24. [Google Scholar] [CrossRef] [PubMed]
  82. Nestler, J.E.; Jakubowicz, D.J.; Falcon de Vargas, A.; Brik, C.; Quintero, N.; Medina, F. Insulin Stimulates Testosterone Biosynthesis by Human Thecal Cells from Women with Polycystic Ovary Syndrome by Activating Its Own Receptor and Using Inositolglycan Mediators as the Signal Transduction System. J. Clin. Endocrinol. Metab. 1998, 83, 2001–2005. [Google Scholar] [CrossRef]
  83. Nestler, J.E.; Powers, L.P.; Matt, D.W.; Steingold, K.A.; Plymate, S.R.; Rittmaster, R.S.; Clore, J.N.; Blackard, W.G. A Direct Effect of Hyperinsulinemia on Serum Sex Hormone-Binding Globulin Levels in Obese Women with the Polycystic Ovary Syndrome. J. Clin. Endocrinol. Metab. 1991, 72, 83–89. [Google Scholar] [CrossRef]
  84. Plymate, S.R.; Matej, L.A.; Jones, R.E.; Friedl, K.E. Inhibition of Sex Hormone-Binding Globulin Production in the Human Hepatoma (Hep G2) Cell Line by Insulin and Prolactin. J. Clin. Endocrinol. Metab. 1988, 67, 460–464. [Google Scholar] [CrossRef]
  85. Sanchez-Garrido, M.A.; Tena-Sempere, M. Metabolic Dysfunction in Polycystic Ovary Syndrome: Pathogenic Role of Androgen Excess and Potential Therapeutic Strategies. Mol. Metab. 2020, 35, 100937. [Google Scholar] [CrossRef]
  86. Panidis, D.; Rousso, D.; Koliakos, G.; Kourtis, A.; Katsikis, I.; Farmakiotis, D.; Votsi, E.; Diamanti-Kandarakis, E. Plasma Metastin Levels Are Negatively Correlated with Insulin Resistance and Free Androgens in Women with Polycystic Ovary Syndrome. Fertil. Steril. 2006, 85, 1778–1783. [Google Scholar] [CrossRef] [PubMed]
  87. Polak, K.; Czyzyk, A.; Simoncini, T.; Meczekalski, B. New Markers of Insulin Resistance in Polycystic Ovary Syndrome. J. Endocrinol. Investig. 2017, 40, 1–8. [Google Scholar] [CrossRef] [PubMed]
  88. Shahin, L.; Hyassat, D.; Batieha, A.; Khader, Y.; El-Khateeb, M.; Ajlouni, K. Insulin Sensitivity Indices in Patients with Polycystic Ovary Syndrome with Different Body Mass Index Categories. Curr. Diabetes Rev. 2020, 16, 483–489. [Google Scholar] [CrossRef] [PubMed]
  89. Vrbíková, J.; Cibula, D.; Dvořáková, K.; Stanická, S.; Šindelka, G.; Hill, M.; Fanta, M.; Vondra, K.; Škrha, J. Insulin Sensitivity in Women with Polycystic Ovary Syndrome. J. Clin. Endocrinol. Metab. 2004, 89, 2942–2945. [Google Scholar] [CrossRef]
  90. Cozzolino, M.; Seli, E. Mitochondrial Function in Women with Polycystic Ovary Syndrome. Curr. Opin. Obstet. Gynecol. 2020, 32, 205–212. [Google Scholar] [CrossRef]
  91. Kumar, D.; Shankar, K.; Patel, S.; Gupta, A.; Varshney, S.; Gupta, S.; Rajan, S.; Srivastava, A.; Vishwakarma, A.L.; Gaikwad, A.N. Chronic Hyperinsulinemia Promotes Meta-Inflammation and Extracellular Matrix Deposition in Adipose Tissue: Implications of Nitric Oxide. Mol. Cell Endocrinol. 2018, 477, 15–28. [Google Scholar] [CrossRef] [PubMed]
  92. Oróstica, L.; García, P.; Vera, C.; García, V.; Romero, C.; Vega, M. Effect of TNF-α on Molecules Related to the Insulin Action in Endometrial Cells Exposed to Hyperandrogenic and Hyperinsulinic Conditions Characteristics of Polycystic Ovary Syndrome. Reprod. Sci. 2018, 25, 1000–1009. [Google Scholar] [CrossRef]
  93. Igosheva, N.; Abramov, A.Y.; Poston, L.; Eckert, J.J.; Fleming, T.P.; Duchen, M.R.; McConnell, J. Maternal Diet-Induced Obesity Alters Mitochondrial Activity and Redox Status in Mouse Oocytes and Zygotes. PLoS ONE 2010, 5, e10074. [Google Scholar] [CrossRef] [PubMed]
  94. Dandona, P.; Mohanty, P.; Ghanim, H.; Aljada, A.; Browne, R.; Hamouda, W.; Prabhala, A.; Afzal, A.; Garg, R. The Suppressive Effect of Dietary Restriction and Weight Loss in the Obese on the Generation of Reactive Oxygen Species by Leukocytes, Lipid Peroxidation, and Protein Carbonylation. J. Clin. Endocrinol. Metab. 2001, 86, 355–362. [Google Scholar] [CrossRef] [PubMed]
  95. Sabuncu, T.; Vural, H.; Harma, M.; Harma, M. Oxidative Stress in Polycystic Ovary Syndrome and Its Contribution to the Risk of Cardiovascular Disease. Clin. Biochem. 2001, 34, 407–413. [Google Scholar] [CrossRef]
  96. González, F.; Rote, N.S.; Minium, J.; Kirwan, J.P. Reactive Oxygen Species-Induced Oxidative Stress in the Development of Insulin Resistance and Hyperandrogenism in Polycystic Ovary Syndrome. J. Clin. Endocrinol. Metab. 2006, 91, 336–340. [Google Scholar] [CrossRef] [PubMed]
  97. Gayoso-Diz, P.; Otero-González, A.; Rodriguez-Alvarez, M.X.; Gude, F.; García, F.; De Francisco, A.; Quintela, A.G. Insulin Resistance (HOMA-IR) Cut-off Values and the Metabolic Syndrome in a General Adult Population: Effect of Gender and Age: EPIRCE Cross-Sectional Study. BMC Endocr. Disord. 2013, 13, 47. [Google Scholar] [CrossRef]
  98. Shimizu, I.; Yoshida, Y.; Katsuno, T.; Tateno, K.; Okada, S.; Moriya, J.; Yokoyama, M.; Nojima, A.; Ito, T.; Zechner, R.; et al. P53-Induced Adipose Tissue Inflammation Is Critically Involved in the Development of Insulin Resistance in Heart Failure. Cell Metab. 2012, 15, 51–64. [Google Scholar] [CrossRef]
  99. Anagnostis, P.; Tarlatzis, B.C.; Kauffman, R.P. Polycystic Ovarian Syndrome (PCOS): Long-Term Metabolic Consequences. Metabolism 2018, 86, 33–43. [Google Scholar] [CrossRef]
  100. Kelley, C.E.; Brown, A.J.; Diehl, A.M.; Setji, T.L. Review of Nonalcoholic Fatty Liver Disease in Women with Polycystic Ovary Syndrome. World J. Gastroenterol. 2014, 20, 14172–14184. [Google Scholar] [CrossRef]
  101. Nandi, A.; Chen, Z.; Patel, R.; Poretsky, L. Polycystic Ovary Syndrome. Endocrinol. Metab. Clin. N. Am. 2014, 43, 123–147. [Google Scholar] [CrossRef] [PubMed]
  102. Wang, J.; Wu, D.; Guo, H.; Li, M. Hyperandrogenemia and Insulin Resistance: The Chief Culprit of Polycystic Ovary Syndrome. Life Sci. 2019, 236, 123–147. [Google Scholar] [CrossRef]
  103. Savage, D.B.; Petersen, K.F.; Shulman, G.I. Disordered Lipid Metabolism and the Pathogenesis of Insulin Resistance. Physiol. Rev. 2007, 87, 507–520. [Google Scholar] [CrossRef]
  104. Pirwany, I.R.; Fleming, R.; Greer, I.A.; Packard, C.J.; Sattar, N. Lipids and Lipoprotein Subfractions in Women with PCOS: Relationship to Metabolic and Endocrine Parameters. Clin. Endocrinol. 2001, 54, 447–453. [Google Scholar] [CrossRef] [PubMed]
  105. Essah, P.A.; Nestler, J.E.; Carmina, E. Differences in Dyslipidemia between American and Italian Women with Polycystic Ovary Syndrome. J. Endocrinol. Investig. 2008, 31, 35–41. [Google Scholar] [CrossRef]
  106. Tziomalos, K.G.; Athyros, V.; Karagiannis, A. Non-Alcoholic Fatty Liver Disease in Type 2 Diabetes: Pathogenesis and Treatment Options. Curr. Vasc. Pharmacol. 2012, 10, 162–172. [Google Scholar] [CrossRef]
  107. Macut, D.; Bjekić-Macut, J.; Rahelić, D.; Doknić, M. Insulin and the Polycystic Ovary Syndrome. Diabetes Res. Clin. Pract. 2017, 130, 163–170. [Google Scholar] [CrossRef] [PubMed]
  108. Baranova, A.; Tran, T.P.; Afendy, A.; Wang, L.; Shamsaddini, A.; Mehta, R.; Chandhoke, V.; Birerdinc, A.; Younossi, Z.M. Molecular Signature of Adipose Tissue in Patients with Both Non-Alcoholic Fatty Liver Disease (NAFLD) and Polycystic Ovarian Syndrome (PCOS). J. Transl. Med. 2013, 11, 133. [Google Scholar] [CrossRef]
  109. Gunter, M.J.; Hoover, D.R.; Yu, H.; Wassertheil-Smoller, S.; Manson, J.E.; Li, J.; Harris, T.G.; Rohan, T.E.; Xue, X.N.; Ho, G.Y.F.; et al. A Prospective Evaluation of Insulin and Insulin-like Growth Factor-I as Risk Factors for Endometrial Cancer. Cancer Epidemiol. Biomarkers Prev. 2008, 17, 921–929. [Google Scholar] [CrossRef]
  110. Rivero, R.; Garin, C.A.; Ormazabal, P.; Silva, A.; Carvajal, R.; Gabler, F.; Romero, C.; Vega, M. Protein Expression of PKCZ (Protein Kinase C Zeta), Munc18c, and Syntaxin-4 in the Insulin Pathway in Endometria of Patients with Polycystic Ovary Syndrome (PCOS). Reprod. Biol. Endocrinol. 2012, 10, 17. [Google Scholar] [CrossRef]
  111. Lee, S.H.; Chung, D.J.; Lee, H.S.; Kim, T.J.; Kim, M.H.; Jeong, H.J.; Im, J.A.; Lee, D.C.; Lee, J.W. Mitochondrial DNA Copy Number in Peripheral Blood in Polycystic Ovary Syndrome. Metabolism 2011, 60, 1677–1682. [Google Scholar] [CrossRef] [PubMed]
  112. Reddy, T.V.; Govatati, S.; Deenadayal, M.; Sisinthy, S.; Bhanoori, M. Impact of Mitochondrial DNA Copy Number and Displacement Loop Alterations on Polycystic Ovary Syndrome Risk in South Indian Women. Mitochondrion 2019, 44, 35–40. [Google Scholar] [CrossRef]
  113. Pruett, J.E.; Everman, S.J.; Hoang, N.H.; Salau, F.; Taylor, L.C.; Edwards, K.S.; Hosler, J.P.; Huffman, A.M.; Romero, D.G.; Yanes Cardozo, L.L. Mitochondrial Function and Oxidative Stress in White Adipose Tissue in a Rat Model of PCOS: Effect of SGLT2 Inhibition. Biol. Sex. Differ. 2022, 13, 45. [Google Scholar] [CrossRef] [PubMed]
  114. Chen, W.; Zhao, H.; Li, Y. Mitochondrial Dynamics in Health and Disease: Mechanisms and Potential Targets. Signal Transduct. Target. Ther. 2023, 8, 333. [Google Scholar] [CrossRef]
  115. Shukla, P.; Dange, P.; Mohanty, B.S.; Gadewal, N.; Chaudhari, P.; Sarin, R. ARID2 Suppression Promotes Tumor Progression and Upregulates Cytokeratin 8, 18 and β-4 Integrin Expression in TP53-Mutated Tobacco-Related Oral Cancer and Has Prognostic Implications. Cancer Gene Ther. 2022, 29, 1908–1917. [Google Scholar] [CrossRef]
  116. Tauffenberger, A.; Magistretti, P.J. Reactive Oxygen Species: Beyond Their Reactive Behavior. Neurochem. Res. 2021, 46, 77–87. [Google Scholar] [CrossRef] [PubMed]
  117. Zhang, J. Mitochondrial DNA copy number variation and gene mutations mediate polycystic ovary syndrome: Research progress. Am. J. Transl. Res. 2024, 16, 6303–6313. [Google Scholar] [CrossRef]
  118. Ding, Y.; Xia, B.H.; Zhang, C.J.; Zhuo, G.C. Mutations in Mitochondrial TRNA Genes May Be Related to Insulin Resistance in Women with Polycystic Ovary Syndrome. Am. J. Transl. Res. 2017, 9, 2984. [Google Scholar]
  119. Lai, Q.; Xiang, W.; Li, Q.; Zhang, H.; Li, Y.; Zhu, G.; Xiong, C.; Jin, L. Oxidative Stress in Granulosa Cells Contributes to Poor Oocyte Quality and IVF-ET Outcomes in Women with Polycystic Ovary Syndrome. Front. Med. 2018, 12, 518–524. [Google Scholar] [CrossRef]
  120. Ernst, E.H.; Lykke-Hartmann, K. Transcripts Encoding Free Radical Scavengers in Human Granulosa Cells from Primordial and Primary Ovarian Follicles. J. Assist. Reprod. Genet. 2018, 35, 1787–1798. [Google Scholar] [CrossRef]
  121. Zeng, X.; Huang, Q.; Long, S.L.; Zhong, Q.; Mo, Z. Mitochondrial Dysfunction in Polycystic Ovary Syndrome. DNA Cell Biol. 2020, 39, 1401–1409. [Google Scholar] [CrossRef]
  122. Zhao, H.; Zhao, Y.; Li, T.; Li, M.; Li, J.; Li, R.; Liu, P.; Yu, Y.; Qiao, J. Metabolism alteration in follicular niche: The nexus among intermediary metabolism, mitochondrial function, and classic polycystic ovary syndrome. Free Radic. Biol. Med. 2015, 86, 295–307. [Google Scholar] [CrossRef]
  123. Luca, T.; Pezzino, S.; Puleo, S.; Castorina, S. Lesson on obesity and anatomy of adipose tissue: New models of study in the era of clinical and translational research. J. Transl. Med. 2024, 22, 1–18. [Google Scholar] [CrossRef]
  124. Horvath, T.L.; Andrews, Z.B.; Diano, S. Fuel Utilization by Hypothalamic Neurons: Roles for ROS. Trends Endocrinol. Metab. 2009, 20, 78–87. [Google Scholar] [CrossRef]
  125. Malin, S.K.; Kirwan, J.P.; Sia, C.L.; González, F. Glucose-Stimulated Oxidative Stress in Mononuclear Cells Is Related to Pancreatic β-Cell Dysfunction in Polycystic Ovary Syndrome. J. Clin. Endocrinol. Metab. 2014, 99, 322–329. [Google Scholar] [CrossRef]
  126. Barnes, P.J.; Karin, M. Nuclear Factor-KappaB: A Pivotal Transcription Factor in Chronic Inflammatory Diseases. N. Engl. J. Med. 1997, 336, 1066–1071. [Google Scholar] [CrossRef]
  127. Anusree, S.S.; Nisha, V.M.; Priyanka, A.; Raghu, K.G. Insulin Resistance by TNF-α Is Associated with Mitochondrial Dysfunction in 3T3-L1 Adipocytes and Is Ameliorated by Punicic Acid, a PPARγ Agonist. Mol. Cell Endocrinol. 2015, 413, 120–128. [Google Scholar] [CrossRef]
  128. Victor, V.M.; Rovira-Llopis, S.; Bañuls, C.; Diaz-Morales, N.; De Marañon, A.M.; Rios-Navarro, C.; Alvarez, A.; Gomez, M.; Rocha, M.; Hernández-Mijares, A. Insulin Resistance in PCOS Patients Enhances Oxidative Stress and Leukocyte Adhesion: Role of Myeloperoxidase. PLoS ONE 2016, 11, e0151960. [Google Scholar] [CrossRef]
  129. Konopka, A.R.; Asante, A.; Lanza, I.R.; Robinson, M.M.; Johnson, M.L.; Man, C.D.; Cobelli, C.; Amols, M.H.; Irving, B.A.; Nair, K.S. Defects in Mitochondrial Efficiency and H2O2 Emissions in Obese Women Are Restored to a Lean Phenotype with Aerobic Exercise Training. Diabetes 2015, 64, 2104–2115. [Google Scholar] [CrossRef]
  130. Skov, V.; Glintborg, D.; Knudsen, S.; Jensen, T.; Kruse, T.A.; Tan, Q.; Brusgaard, K.; Beck-Nielsen, H.; Højlund, K. Reduced Expression of Nuclear-Encoded Genes Involved in Mitochondrial Oxidative Metabolism in Skeletal Muscle of Insulin-Resistant Women with Polycystic Ovary Syndrome. Diabetes 2007, 56, 2349–2355. [Google Scholar] [CrossRef]
  131. Boots, C.E.; Boudoures, A.; Zhang, W.; Drury, A.; Moley, K.H. Obesity-Induced Oocyte Mitochondrial Defects Are Partially Prevented and Rescued by Supplementation with Co-Enzyme Q10 in a Mouse Model. Hum. Reprod. 2016, 31, 2090–2097. [Google Scholar] [CrossRef]
  132. Rabøl, R.; Svendsen, P.F.; Skovbro, M.; Boushel, R.; Schjerling, P.; Nilas, L.; Madsbad, S.; Dela, F. Skeletal Muscle Mitochondrial Function in Polycystic Ovarian Syndrome. Eur. J. Endocrinol. 2011, 165, 631–637. [Google Scholar] [CrossRef]
  133. Liu, X.; Trakooljul, N.; Hadlich, F.; Murani, E.; Wimmers, K.; Ponsuksili, S. Mitochondrial-Nuclear Crosstalk, Haplotype and Copy Number Variation Distinct in Muscle Fiber Type, Mitochondrial Respiratory and Metabolic Enzyme Activities. Sci. Rep. 2017, 7, 14024. [Google Scholar] [CrossRef]
  134. De Marco, G.; Garcia-Garcia, A.B.; Real, J.T.; Gonzalez-Albert, V.; Briongos-Figuero, L.S.; Cobos-Siles, M.; Lago-Sampedro, A.; Corbaton, A.; Teresa Martinez-Larrad, M.; Carmena, R.; et al. Respiratory Chain Polymorphisms and Obesity in the Spanish Population, a Cross-Sectional Study. BMJ Open 2019, 9, e027004. [Google Scholar] [CrossRef]
  135. Reddy, T.V.; Govatati, S.; Deenadayal, M.; Shivaji, S.; Bhanoori, M. Polymorphisms in the TFAM and PGC1-α Genes and Their Association with Polycystic Ovary Syndrome among South Indian Women. Gene 2018, 641, 129–136. [Google Scholar] [CrossRef]
  136. Tharayil, S.P.; Rasal, S.; Gawde, U.; Mukherjee, S.; Patil, A.; Joshi, B.; Idicula-Thomas, S.; Shukla, P. Relation of mitochondrial DNA copy number and variants with the clinical characteristics of polycystic ovary syndrome. Mol. Cell Endocrinol. 2024, 594, 112386. [Google Scholar] [CrossRef]
  137. Deng, X.; Ji, D.; Li, X.; Xu, Y.; Cao, Y.; Zou, W.; Liang, C.; Lee Marley, J.; Zhang, Z.; Wei, Z.; et al. Polymorphisms and Haplotype of Mitochondrial DNA D-Loop Region Are Associated with Polycystic Ovary Syndrome in a Chinese Population. Mitochondrion 2021, 57, 173–181. [Google Scholar] [CrossRef]
  138. Zhuo, G.; Ding, Y.; Feng, G.; Yu, L.; Jiang, Y. Analysis of Mitochondrial DNA Sequence Variants in Patients with Polycystic Ovary Syndrome. Arch. Gynecol. Obstet. 2012, 286, 653–659. [Google Scholar] [CrossRef]
  139. Zhu, J.; Vinothkumar, K.R.; Hirst, J. Structure of Mammalian Respiratory Complex I. Nature 2016, 536, 354–358. [Google Scholar] [CrossRef]
  140. Kokaze, A.; Ishikawa, M.; Matsunaga, N.; Yoshida, M.; Sekine, Y.; Sekiguchi, K.; Harada, M.; Satoh, M.; Teruya, K.; Takeda, N.; et al. Longevity-Associated Mitochondrial DNA 5178 A/C Polymorphism and Blood Pressure in the Japanese Population. J. Hum. Hypertens. 2004, 18, 41–45. [Google Scholar] [CrossRef]
  141. Mukae, S.; Aoki, S.; Itoh, S.; Sato, R.; Nishio, K.; Iwata, T.; Katagiri, T. Mitochondrial 5178A/C Genotype Is Associated with Acute Myocardial Infarction. Circ. J. 2003, 67, 16–20. [Google Scholar] [CrossRef]
  142. Jiang, Z.; Teng, L.; Zhang, S.; Ding, Y. Mitochondrial ND1 T4216C and ND2 C5178A Mutations Are Associated with Maternally Transmitted Diabetes Mellitus. Mitochondrial DNA Part A 2021, 32, 59–65. [Google Scholar] [CrossRef]
  143. Ding, Y.; Zhuo, G.; Zhang, C.; Leng, J. Point Mutation in Mitochondrial TRNA Gene Is Associated with Polycystic Ovary Syndrome and Insulin Resistance. Mol. Med. Rep. 2016, 13, 3169–3172. [Google Scholar] [CrossRef]
  144. Jiang, Z.; Cai, X.; Kong, J.; Zhang, R.; Ding, Y. Maternally Transmitted Diabetes Mellitus May Be Associated with Mitochondrial ND5 T12338C and TRNAAla T5587C Variants. Ir. J. Med. Sci. 2022, 191, 2625–2633. [Google Scholar] [CrossRef]
  145. Zhang, J.; Ji, Y.; Lu, Y.; Fu, R.; Xu, M.; Liu, X.; Guan, M.X. Leber’s Hereditary Optic Neuropathy (LHON)-Associated ND5 12338T > C Mutation Altered the Assembly and Function of Complex I, Apoptosis and Mitophagy. Hum. Mol. Genet. 2018, 27, 1999–2011. [Google Scholar] [CrossRef]
  146. Huoponen, K.; Lamminen, T.; Juvonen, V.; Aula, P.; Nikoskelainen, E.; Savontaus, M.L. The Spectrum of Mitochondrial DNA Mutations in Families with Leber Hereditary Optic Neuroretinopathy. Hum. Genet. 1993, 92, 379–384. [Google Scholar] [CrossRef]
  147. Rinaldi, T.; Lande, R.; Bolotin-Fukuhara, M.; Frontali, L. Additional Copies of the Mitochondrial Ef-Tu and Aspartyl-TRNA Synthetase Genes Can Compensate for a Mutation Affecting the Maturation of the Mitochondrial TRNAAsp. Curr. Genet. 1997, 31, 494–496. [Google Scholar] [CrossRef]
  148. Belostotsky, R.; Frishberg, Y.; Entelis, N. Human Mitochondrial TRNA Quality Control in Health and Disease: A Channelling Mechanism? RNA Biol. 2012, 9, 33–39. [Google Scholar] [CrossRef]
  149. Ye, M.; Hu, B.; Shi, W.; Guo, F.; Xu, C.; Li, S. Mitochondrial DNA 4977 Bp in Peripheral Blood Is Associated with Polycystic Ovary Syndrome. Front. Endocrinol. 2021, 12, 675581. [Google Scholar] [CrossRef]
  150. Saeed, N.A.H.A.A.H.; Hamzah, I.H.; Al-Gharrawi, S.A.R. Polycystic Ovary Syndrome Dependency on MtDNA Mutation; Copy Number and Its Association with Insulin Resistance. BMC Res. Notes 2019, 12, 455. [Google Scholar] [CrossRef]
  151. He, S.; Ji, D.; Liu, Y.; Deng, X.; Zou, W.; Liang, D.; Du, Y.; Zong, K.; Jiang, T.; Li, M.; et al. Polymorphisms of MtDNA in the D-Loop Region Moderate the Associations of BMI with HOMA-IR and HOMA-β among Women with Polycystic Ovary Syndrome: A Cross-Sectional Study. J. Assist. Reprod. Genet. 2023, 40, 1983–1993. [Google Scholar] [CrossRef]
  152. Ilie, I.R. Advances in PCOS Pathogenesis and Progression-Mitochondrial Mutations and Dysfunction. Adv. Clin. Chem. 2018, 86, 127–155. [Google Scholar] [CrossRef]
  153. Teede, H.J.; Misso, M.L.; Costello, M.F.; Dokras, A.; Laven, J.; Moran, L.; Piltonen, T.; Norman, R.J.; Andersen, M.; Azziz, R.; et al. Recommendations from the International Evidence-Based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. Fertil. Steril. 2018, 110, 364–379. [Google Scholar] [CrossRef]
  154. Samadi, Z.; Bambaeichi, E.; Valiani, M.; Shahshahan, Z. Evaluation of Changes in Levels of Hyperandrogenism, Hirsutism and Menstrual Regulation After a Period of Aquatic High Intensity Interval Training in Women with Polycystic Ovary Syndrome. Int. J. Prev. Med. 2019, 10, 187. [Google Scholar] [CrossRef]
  155. Shele, G.; Genkil, J.; Speelman, D. A Systematic Review of the Effects of Exercise on Hormones in Women with Polycystic Ovary Syndrome. J. Funct. Morphol. Kinesiol. 2020, 5, 35. [Google Scholar] [CrossRef]
  156. Dabravolski, S.A.; Nikiforov, N.G.; Eid, A.H.; Nedosugova, L.V.; Starodubova, A.V.; Popkova, T.V.; Bezsonov, E.E.; Orekhov, A.N. Mitochondrial Dysfunction and Chronic Inflammation in Polycystic Ovary Syndrome. Int. J. Mol. Sci. 2021, 22, 3923. [Google Scholar] [CrossRef]
  157. Silva Dantas, W.; Antonio Miguel Marcondes, J.; Katsuyuki Shinjo, S.; Augusto Perandini, L.; Olzon Zambelli, V.; Das Neves, W.; Roberto Grimaldi Barcellos, C.; Patrocínio Rocha, M.; Dos Reis Vieira Yance, V.; Tavares Dos Santos Pereira, R.; et al. GLUT4 Translocation Is Not Impaired after Acute Exercise in Skeletal Muscle of Women with Obesity and Polycystic Ovary Syndrome. Obesity 2015, 23, 2207–2215. [Google Scholar] [CrossRef]
  158. Dantas, W.S.; Murai, I.H.; Perandini, L.A.; Azevedo, H.; Moreira-Filho, C.A.; Camara, N.O.S.; Roschel, H.; Gualano, B. Acute Exercise Elicits Differential Expression of Insulin Resistance Genes in the Skeletal Muscle of Patients with Polycystic Ovary Syndrome. Clin. Endocrinol. 2017, 86, 688–697. [Google Scholar] [CrossRef]
  159. Teede, H.J.; Tay, C.T.; Laven, J.J.E.; Dokras, A.; Moran, L.J.; Piltonen, T.T.; Costello, M.F.; Boivin, J.; Redman, L.M.; Boyle, J.A.; et al. Recommendations From the 2023 International Evidence-Based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. J. Clin. Endocrinol. Metab. 2023, 108, 2447–2469. [Google Scholar] [CrossRef]
  160. Almenning, I.; Rieber-Mohn, A.; Lundgren, K.M.; Løvvik, T.S.; Garnæs, K.K.; Moholdt, T. Effects of High Intensity Interval Training and Strength Training on Metabolic, Cardiovascular and Hormonal Outcomes in Women with Polycystic Ovary Syndrome: A Pilot Study. PLoS ONE 2015, 10, e0138793. [Google Scholar] [CrossRef]
  161. García-Prieto, C.F.; Fernández-Alfonso, M.S. Caloric Restriction as a Strategy to Improve Vascular Dysfunction in Metabolic Disorders. Nutrients 2016, 8, 370. [Google Scholar] [CrossRef]
  162. Dengel, D.R.; Pratley, R.E.; Hagberg, J.M.; Rogus, E.M.; Goldberg, A.P. Distinct Effects of Aerobic Exercise Training and Weight Loss on Glucose Homeostasis in Obese Sedentary Men. J. Appl. Physiol. 1996, 81, 318–325. [Google Scholar] [CrossRef]
  163. Weiss, E.P.; Racette, S.B.; Villareal, D.T.; Fontana, L.; Steger-May, K.; Schechtman, K.B.; Klein, S.; Holloszy, J.O. Improvements in Glucose Tolerance and Insulin Action Induced by Increasing Energy Expenditure or Decreasing Energy Intake: A Randomized Controlled Trial. Am. J. Clin. Nutr. 2006, 84, 1033–1042. [Google Scholar] [CrossRef]
  164. Larson-Meyer, D.E.; Heilbronn, L.K.; Redman, L.M.; Newcomer, B.R.; Frisard, M.I.; Anton, S.; Smith, S.R.; Alfonso, A.; Ravussin, E. Effect of Calorie Restriction with or without Exercise on Insulin Sensitivity, Beta-Cell Function, Fat Cell Size, and Ectopic Lipid in Overweight Subjects. Diabetes Care 2006, 29, 1337–1344. [Google Scholar] [CrossRef]
  165. Kitada, M.; Kume, S.; Takeda-Watanabe, A.; Tsuda, S.I.; Kanasaki, K.; Koya, D. Calorie Restriction in Overweight Males Ameliorates Obesity-Related Metabolic Alterations and Cellular Adaptations through Anti-Aging Effects, Possibly Including AMPK and SIRT1 Activation. Biochim. Biophys. Acta 2013, 1830, 4820–4827. [Google Scholar] [CrossRef]
  166. Schenk, S.; McCurdy, C.E.; Philp, A.; Chen, M.Z.; Holliday, M.J.; Bandyopadhyay, G.K.; Osborn, O.; Baar, K.; Olefsky, J.M. Sirt1 Enhances Skeletal Muscle Insulin Sensitivity in Mice during Caloric Restriction. J. Clin. Investig. 2011, 121, 4281–4288. [Google Scholar] [CrossRef]
  167. Shukla, P.; Melkani, G.C. Mitochondrial Epigenetic Modifications and Nuclear-Mitochondrial Communication: A New Dimension towards Understanding and Attenuating the Pathogenesis in Women with PCOS. Rev. Endocr. Metab. Disord. 2023, 24, 317–326. [Google Scholar] [CrossRef]
  168. Gu, Y.; Zhou, G.; Zhou, F.; Wu, Q.; Ma, C.; Zhang, Y.; Ding, J.; Hua, K. Life Modifications and PCOS: Old Story But New Tales. Front. Endocrinol. 2022, 13. [Google Scholar] [CrossRef]
  169. Filippou, C.D.; Tsioufis, C.P.; Thomopoulos, C.G.; Mihas, C.C.; Dimitriadis, K.S.; Sotiropoulou, L.I.; Chrysochoou, C.A.; Nihoyannopoulos, P.I.; Tousoulis, D.M. Dietary Approaches to Stop Hypertension (DASH) Diet and Blood Pressure Reduction in Adults with and without Hypertension: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Adv. Nutr. 2020, 11, 1150–1160. [Google Scholar] [CrossRef]
  170. Toh, D.W.K.; Koh, E.S.; Kim, J.E. Lowering Breakfast Glycemic Index and Glycemic Load Attenuates Postprandial Glycemic Response: A Systematically Searched Meta-Analysis of Randomized Controlled Trials. Nutrition 2020, 71, 110634. [Google Scholar] [CrossRef]
  171. Schwingshackl, L.; Hoffmann, G. Long-Term Effects of Low Glycemic Index/Load vs. High Glycemic Index/Load Diets on Parameters of Obesity and Obesity-Associated Risks: A Systematic Review and Meta-Analysis. Nutr. Metab. Cardiovasc. Dis. 2013, 23, 699–706. [Google Scholar] [CrossRef]
  172. Damsgaard, C.T.; Biltoft-Jensen, A.; Tetens, I.; Michaelsen, K.F.; Lind, M.V.; Astrup, A.; Landberg, R. Whole-Grain Intake, Reflected by Dietary Records and Biomarkers, Is Inversely Associated with Circulating Insulin and Other Cardiometabolic Markers in 8- to 11-Year-Old Children. J. Nutr. 2017, 147, 816–824. [Google Scholar] [CrossRef]
  173. Heikkilä, H.M.; Krachler, B.; Rauramaa, R.; Schwab, U.S. Diet, Insulin Secretion and Insulin Sensitivity--the Dose-Responses to Exercise Training (DR’s EXTRA) Study (ISRCTN45977199). Br. J. Nutr. 2014, 112, 1530–1541. [Google Scholar] [CrossRef]
  174. Vlassara, H.; Cai, W.; Tripp, E.; Pyzik, R.; Yee, K.; Goldberg, L.; Tansman, L.; Chen, X.; Mani, V.; Fayad, Z.A.; et al. Oral AGE Restriction Ameliorates Insulin Resistance in Obese Individuals with the Metabolic Syndrome: A Randomised Controlled Trial. Diabetologia 2016, 59, 2181–2192. [Google Scholar] [CrossRef] [PubMed]
  175. Rothenberg, S.S.; Beverley, R.; Barnard, E.; Baradaran-Shoraka, M.; Sanfilippo, J.S. Polycystic Ovary Syndrome in Adolescents. Best. Pract. Res. Clin. Obstet. Gynaecol. 2018, 48, 103–114. [Google Scholar] [CrossRef]
  176. Armanini, D.; Boscaro, M.; Bordin, L.; Sabbadin, C. Controversies in the Pathogenesis, Diagnosis and Treatment of PCOS: Focus on Insulin Resistance, Inflammation, and Hyperandrogenism. Int. J. Mol. Sci. 2022, 23, 4110. [Google Scholar] [CrossRef] [PubMed]
  177. Homburg, R.; Eshel, A.; Abdalla, H.I.; Jacobs, H.S. Growth Hormone Facilitates Ovulation Induction by Gonadotrophins. Clin. Endocrinol. 1988, 29, 113–117. [Google Scholar] [CrossRef]
  178. Gong, Y.; Luo, S.; Fan, P.; Jin, S.; Zhu, H.; Deng, T.; Quan, Y.; Huang, W. Growth Hormone Alleviates Oxidative Stress and Improves Oocyte Quality in Chinese Women with Polycystic Ovary Syndrome: A Randomized Controlled Trial. Sci. Rep. 2020, 10, 18769. [Google Scholar] [CrossRef]
  179. Balen, A.H.; Morley, L.C.; Misso, M.; Franks, S.; Legro, R.S.; Wijeyaratne, C.N.; Stener-Victorin, E.; Fauser, B.C.J.M.; Norman, R.J.; Teede, H. The Management of Anovulatory Infertility in Women with Polycystic Ovary Syndrome: An Analysis of the Evidence to Support the Development of Global WHO Guidance. Hum. Reprod. Update 2016, 22, 687–708. [Google Scholar] [CrossRef]
  180. Escobar-Morreale, H.F. Polycystic Ovary Syndrome: Definition, Aetiology, Diagnosis and Treatment. Nat. Rev. Endocrinol. 2018, 14, 270–284. [Google Scholar] [CrossRef]
  181. Foretz, M.; Guigas, B.; Bertrand, L.; Pollak, M.; Viollet, B. Metformin: From Mechanisms of Action to Therapies. Cell Metab. 2014, 20, 953–966. [Google Scholar] [CrossRef] [PubMed]
  182. Luz, M.; Albarracín, G.; Yibby, A.; Torres, F.; Albarracin, G. Adiponectin and Leptin Adipocytokines in Metabolic Syndrome: What Is Its Importance? Dubai Diabetes Endocrinol. J. 2020, 26, 93–102. [Google Scholar] [CrossRef]
  183. Azziz, R.; Carmina, E.; Chen, Z.; Dunaif, A.; Laven, J.S.E.; Legro, R.S.; Lizneva, D.; Natterson-Horowtiz, B.; Teede, H.J.; Yildiz, B.O. Polycystic Ovary Syndrome. Nat. Rev. Dis. Primers 2016, 2, 16057. [Google Scholar] [CrossRef]
  184. Legro, R.S.; Arslanian, S.A.; Ehrmann, D.A.; Hoeger, K.M.; Murad, M.H.; Pasquali, R.; Welt, C.K. Diagnosis and Treatment of Polycystic Ovary Syndrome: An Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 2013, 98, 4565–4592. [Google Scholar] [CrossRef]
  185. Donà, G.; Sabbadin, C.; Fiore, C.; Bragadin, M.; Giorgino, F.L.; Ragazzi, E.; Clari, G.; Bordin, L.; Armanini, D. Inositol Administration Reduces Oxidative Stress in Erythrocytes of Patients with Polycystic Ovary Syndrome. Eur. J. Endocrinol. 2012, 166, 703–710. [Google Scholar] [CrossRef]
  186. Dinicola, S.; Unfer, V.; Facchinetti, F.; Soulage, C.O.; Greene, N.D.; Bizzarri, M.; Laganà, A.S.; Chan, S.Y.; Bevilacqua, A.; Pkhaladze, L.; et al. Inositols: From Established Knowledge to Novel Approaches. Int. J. Mol. Sci. 2021, 22, 10575. [Google Scholar] [CrossRef]
  187. Tentolouris, A.; Vlachakis, P.; Tzeravini, E.; Eleftheriadou, I.; Tentolouris, N. SGLT2 Inhibitors: A Review of Their Antidiabetic and Cardioprotective Effects. Int. J. Environ. Res. Public. Health 2019, 16, 2965. [Google Scholar] [CrossRef] [PubMed]
  188. Marinkovic-Radosevic, J.; Cigrovski Berkovic, M.; Kruezi, E.; Bilic-Curcic, I.; Mrzljak, A. Exploring New Treatment Options for Polycystic Ovary Syndrome: Review of a Novel Antidiabetic Agent SGLT2 Inhibitor. World J. Diabetes 2021, 12, 932–938. [Google Scholar] [CrossRef]
  189. Jiang, S.; Tang, T.; Sheng, Y.; Li, R.; Xu, H. The Effects of Letrozole and Metformin Combined with Targeted Nursing Care on Ovarian Function, LH, and FSH in Infertile Patients with Polycystic Ovary Syndrome. J. Healthc. Eng. 2022, 2022, 3712166. [Google Scholar] [CrossRef]
  190. Unluhizarci, K.; Karaca, Z.; Kelestimur, F. Role of Insulin and Insulin Resistance in Androgen Excess Disorders. World J. Diabetes 2021, 12, 616. [Google Scholar] [CrossRef]
  191. Patel, S. Polycystic Ovary Syndrome (PCOS), an Inflammatory, Systemic, Lifestyle Endocrinopathy. J. Steroid Biochem. Mol. Biol. 2018, 182, 27–36. [Google Scholar] [CrossRef] [PubMed]
  192. Wang, J.G.; Anderson, R.A.; Graham, G.M.; Chu, M.C.; Sauer, M.V.; Guarnaccia, M.M.; Lobo, R.A. The Effect of Cinnamon Extract on Insulin Resistance Parameters in Polycystic Ovary Syndrome: A Pilot Study. Fertil. Steril. 2007, 88, 240–243. [Google Scholar] [CrossRef]
  193. Nabiuni, M.; Kayedpoor, P.; Mohammadi, S.; Karimzadeh, L. Effect of Silymarin on Estradiol Valerate- Induced Polycystic Ovary Syndrome. Med. Sci. J. Islam. Azad Univesity—Tehran Med. Branch 2015, 25, 16–26. [Google Scholar]
  194. Azhar, A.; Haider, G.; Naseem, Z.; Farooqui, N.; Farooqui, M.U.; Rehman, R. Morphological Changes in the Experimental Model of Polycystic Ovary Syndrome and Effects of Vitamin D Treatment. J. Obstet. Gynaecol. Res. 2021, 47, 1164–1171. [Google Scholar] [CrossRef]
  195. Safaei, Z.; Bakhshalizadeh, S.; Nasr-Esfahani, M.H.; Akbari Sene, A.; Najafzadeh, V.; Soleimani, M.; Shirazi, R. Vitamin D3 Affects Mitochondrial Biogenesis through Mitogen-Activated Protein Kinase in Polycystic Ovary Syndrome Mouse Model. J. Cell Physiol. 2020, 235, 6113–6126. [Google Scholar] [CrossRef]
  196. Gao, Y.; Zou, Y.; Wu, G.; Zheng, L. Oxidative Stress and Mitochondrial Dysfunction of Granulosa Cells in Polycystic Ovarian Syndrome. Front. Med. 2023, 10, 1193749. [Google Scholar] [CrossRef]
  197. Ding, Y.; Jiang, Z.; Xia, B.; Zhang, L.; Zhang, C.; Leng, J. Mitochondria-Targeted Antioxidant Therapy for an Animal Model of PCOS-IR. Int. J. Mol. Med. 2019, 43, 316–324. [Google Scholar] [CrossRef] [PubMed]
  198. Wang, Y.; Yang, Q.; Wang, H.; Zhu, J.; Cong, L.; Li, H.; Sun, Y. NAD+ Deficiency and Mitochondrial Dysfunction in Granulosa Cells of Women with Polycystic Ovary Syndrome‡. Biol. Reprod. 2021, 105, 371–380. [Google Scholar] [CrossRef] [PubMed]
  199. Li, L.; Zhou, X.; Liu, W.; Chen, Z.; Xiao, X.; Deng, G. Supplementation with NAD+ and Its Precursors: A Rescue of Female Reproductive Diseases. Biochem. Biophys. Rep. 2024, 38, 101715. [Google Scholar] [CrossRef]
  200. Yen, K.; Lee, C.; Mehta, H.; Cohen, P. The Emerging Role of the Mitochondrial-Derived Peptide Humanin in Stress Resistance. J. Mol. Endocrinol. 2013, 50, R11–R19. [Google Scholar] [CrossRef]
  201. Kim, S.J.; Xiao, J.; Wan, J.; Cohen, P.; Yen, K. Mitochondrially Derived Peptides as Novel Regulators of Metabolism. J. Physiol. 2017, 595, 6613–6621. [Google Scholar] [CrossRef] [PubMed]
  202. Kuliawat, R.; Klein, L.; Gong, Z.; Nicoletta-Gentile, M.; Nemkal, A.; Cui, L.; Bastie, C.; Su, K.; Huffman, D.; Surana, M.; et al. Potent Humanin Analog Increases Glucose-Stimulated Insulin Secretion through Enhanced Metabolism in the β Cell. FASEB J. 2013, 27, 4890–4898. [Google Scholar] [CrossRef] [PubMed]
  203. Muzumdar, R.H.; Huffman, D.M.; Atzmon, G.; Buettner, C.; Cobb, L.J.; Fishman, S.; Budagov, T.; Cui, L.; Einstein, F.H.; Poduval, A.; et al. Humanin: A Novel Central Regulator of Peripheral Insulin Action. PLoS ONE 2009, 4, e6334. [Google Scholar] [CrossRef]
  204. Wang, Y.; Zeng, Z.; Zhao, S.; Tang, L.; Yan, J.; Li, N.; Zou, L.; Fan, X.; Xu, C.; Huang, J.; et al. Humanin Alleviates Insulin Resistance in Polycystic Ovary Syndrome: A Human and Rat Model-Based Study. Endocrinology 2021, 162, bqab056. [Google Scholar] [CrossRef]
  205. Lee, C. Nuclear Transcriptional Regulation by Mitochondrial-Encoded MOTS-c. Mol. Cell Oncol. 2019, 6, 1–2. [Google Scholar] [CrossRef]
  206. Cobb, L.J.; Lee, C.; Xiao, J.; Yen, K.; Wong, R.G.; Nakamura, H.K.; Mehta, H.H.; Gao, Q.; Ashur, C.; Huffman, D.M.; et al. Naturally Occurring Mitochondrial-Derived Peptides Are Age-Dependent Regulators of Apoptosis, Insulin Sensitivity, and Inflammatory Markers. Aging 2016, 8, 796–808. [Google Scholar] [CrossRef] [PubMed]
  207. Hebert, J.F.; Myatt, L. Placental Mitochondrial Dysfunction with Metabolic Diseases: Therapeutic Approaches. Biochim. Biophys. Acta Mol. Basis Dis. 2021, 1867, 165967. [Google Scholar] [CrossRef]
  208. Kolhe, J.V.; Chhipa, A.S.; Butani, S.; Chavda, V.; Patel, S.S. PCOS and Depression: Common Links and Potential Targets. Reprod. Sci. 2022, 29, 3106–3123. [Google Scholar] [CrossRef]
  209. Patel, A.; Dewani, D.; Jaiswal, A.; Yadav, P.; Reddy, L.S. Exploring Melatonin’s Multifaceted Role in Polycystic Ovary Syndrome Management: A Comprehensive Review. Cureus 2023, 15, e48929. [Google Scholar] [CrossRef]
  210. Sam, S.; Tasali, E. Role of obstructive sleep apnea in metabolic risk in PCOS. Curr. Opin. Endocr. Metab. Res. 2021, 17, 46–51. [Google Scholar] [CrossRef]
  211. He, J.; Ruan, X.; Li, J. Polycystic ovary syndrome in obstructive sleep apnea-hypopnea syndrome: An updated meta-analysis. Front. Endocrinol. 2024, 15, 1418933. [Google Scholar] [CrossRef] [PubMed]
  212. Prabhakar, N.R.; Peng, Y.J.; Nanduri, J. Hypoxia-inducible factors and obstructive sleep apnea. J. Clin. Investig. 2020, 130, 5042–5051. [Google Scholar] [CrossRef] [PubMed]
  213. Morimoto, Y.; Gamage, U.S.K.; Yamochi, T.; Saeki, N.; Morimoto, N.; Yamanaka, M.; Koike, A.; Miyamoto, Y.; Tanaka, K.; Fukuda, A.; et al. Mitochondrial Transfer into Human Oocytes Improved Embryo Quality and Clinical Outcomes in Recurrent Pregnancy Failure Cases. Int. J. Mol. Sci. 2023, 24, 2738. [Google Scholar] [CrossRef]
  214. Abdi, A.; Ranjbaran, M.; Amidi, F.; Akhondzadeh, F.; Seifi, B. The Effect of Adipose-Derived Mesenchymal Stem Cell Transplantation on Ovarian Mitochondrial Dysfunction in Letrozole-Induced Polycystic Ovary Syndrome in Rats: The Role of PI3K-AKT Signaling Pathway. J. Ovarian Res. 2024, 17, 1–18. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Diagram illustrating the complex interplay between mitochondrial dysfunction, PCOS, and IR. DAG and CER link mitochondrial dysfunction to IR by activating protein kinase C and inhibiting AKT, respectively, and through increased ROS production. Insulin acts as a co-gonadotropin and enhances LH effects on androgen biosynthesis in ovarian theca cells. Excess insulin inhibits SHBG-release from the liver, increasing free testosterone levels and leading to hyperandrogenaemia, a clinical manifestation of PCOS. IR predisposes women with PCOS to comorbidities such as obesity, CVD, T2D, NAFLD, and EC.
Figure 1. Diagram illustrating the complex interplay between mitochondrial dysfunction, PCOS, and IR. DAG and CER link mitochondrial dysfunction to IR by activating protein kinase C and inhibiting AKT, respectively, and through increased ROS production. Insulin acts as a co-gonadotropin and enhances LH effects on androgen biosynthesis in ovarian theca cells. Excess insulin inhibits SHBG-release from the liver, increasing free testosterone levels and leading to hyperandrogenaemia, a clinical manifestation of PCOS. IR predisposes women with PCOS to comorbidities such as obesity, CVD, T2D, NAFLD, and EC.
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Figure 2. Schematic diagram illustrating diverse present and future therapeutic strategies targeting insulin resistance and mitochondrial dysfunction in PCOS pathophysiology.
Figure 2. Schematic diagram illustrating diverse present and future therapeutic strategies targeting insulin resistance and mitochondrial dysfunction in PCOS pathophysiology.
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Tharayil, S.P.; Shukla, P. Connecting the Dots: Mitochondrial Dysfunction, PCOS, and Insulin Resistance—Insights and Therapeutic Advances. Int. J. Mol. Sci. 2025, 26, 6233. https://doi.org/10.3390/ijms26136233

AMA Style

Tharayil SP, Shukla P. Connecting the Dots: Mitochondrial Dysfunction, PCOS, and Insulin Resistance—Insights and Therapeutic Advances. International Journal of Molecular Sciences. 2025; 26(13):6233. https://doi.org/10.3390/ijms26136233

Chicago/Turabian Style

Tharayil, Samia Palat, and Pallavi Shukla. 2025. "Connecting the Dots: Mitochondrial Dysfunction, PCOS, and Insulin Resistance—Insights and Therapeutic Advances" International Journal of Molecular Sciences 26, no. 13: 6233. https://doi.org/10.3390/ijms26136233

APA Style

Tharayil, S. P., & Shukla, P. (2025). Connecting the Dots: Mitochondrial Dysfunction, PCOS, and Insulin Resistance—Insights and Therapeutic Advances. International Journal of Molecular Sciences, 26(13), 6233. https://doi.org/10.3390/ijms26136233

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