Search Results (328)

T cells play a vital role in resisting pathogen invasion and maintaining immune homeostasis. However, T cells gradually become exhausted under chronic antigenic stimulation, and this exhaustion is closely related to mitochondrial dysfunction in T cells. Mitochondria play a crucial role in the metabolic reprogramming of T cells to achieve the desired immune response. Here, we compiled the latest research on how mitochondrial metabolism determines T cell function and differentiation, with the mechanisms mainly including mitochondrial biogenesis, fission, fusion, mitophagy, and mitochondrial transfer. In addition, the alterations in mitochondrial metabolism in T-cell exhaustion were also reviewed. Furthermore, we discussed intervention strategies targeting mitochondrial metabolism to reverse T cell exhaustion in detail, including inducing PGC-1α expression, alleviating reactive oxygen species (ROS) production or hypoxia, enhancing ATP production, and utilizing mitochondrial transfer. Targeting mitochondrial metabolism in exhausted T cells may achieve the goal of reversing and preventing T cell exhaustion. Full article

Cerebral ischemic-reperfusion injury (CIRI) involves mitochondrial dysfunction, with mitophagy playing a key role. Astragaloside IV (AS-IV) shows neuroprotective potential; however, its mechanisms related to mitochondrial function and apoptosis remain unclear. Methods: Using a rat MCAO/R model, we evaluated the AS-IV’s effects via neurological scores, TTC staining, and histopathology. Molecular assays and docking were used to analyze mitophagy (PINK1, Parkin, p62, ROS, Bcl-2, and BAX) and apoptosis markers. Results: AS-IV improved neurological function, reduced infarct volume, and alleviated neuronal/mitochondrial damage. It upregulated PINK1/Parkin, decreased p62, and modulated Bcl-2/Bax. Docking confirmed AS-IV binds PINK1/Parkin with high affinity. Conclusions: AS-IV protects against CIRI by regulating the PINK1/Parkin pathway, improving mitochondrial function, and inhibiting neuronal apoptosis, providing an experimental basis for the clinical use Full article

Pulmonary arterial hypertension (PAH) is a rare, progressive, and incurable disease characterized by an elevated pulmonary blood pressure, extensive remodeling of the pulmonary vasculature, increased pulmonary vascular resistance, and culminating in right ventricular failure. Mitochondrial dysfunction has a major role in the pathogenesis of PAH and secondary right ventricular failure, and its targeting may offer therapeutic benefit. In this study, we provide proof-of-concept for the use of the mitochondrially active drug SUL-150 to treat PAH. PAH was induced in rats by monocrotaline, followed by the placement of an aortocaval shunt one week later. The mitoprotective compound SUL-150 (~6 mg·kg⁻¹·day⁻¹) or vehicle was administered intraperitoneally via osmotic minipump for 28 days, implanted at the time of aortocaval shunt placement. Vehicle-treated PAH rats had dyspnea and showed pulmonary artery remodeling with increased responsiveness to phenylephrine, in addition to remodeling of the intrapulmonary arterioles. SUL-150 administration mitigated the dyspnea and the remodeling responses. Vehicle-treated PAH rats developed right ventricular hypertrophy, fibrosis, and failure. SUL-150 administration precluded cardiomyocyte hypertrophy and inhibited ventricular fibrogenesis. Right ventricular failure in vehicle-treated PAH rats induced mitochondrial loss and dysfunction associated with a decrease in mitophagy. SUL-150 was unable to prevent the mitochondrial loss but improved mitochondrial health in the right ventricle, which culminated in the preservation of right ventricular function. We conclude that SUL-150 improves PAH-associated morbidity by the amelioration of pulmonary vascular remodeling and right ventricular failure and may be considered a promising therapeutic candidate to slow disease progression in pulmonary arterial hypertension and secondary right ventricular failure. Full article

Dietary advanced glycation end-products (dAGEs) contained in high-sugar/fat and ultra-processed foods of the “Western diet” (WD) pattern predispose to several diseases by altering protein function or increasing oxidative stress and inflammation via RAGE (receptor for advanced glycation end-products). Although elevated endogenous AGEs are associated with loss of muscle mass and functionality (i.e., muscle wasting; MW), the impact of dAGEs on MW has not been elucidated. Here, we show that the most common dAGEs or their precursor, methylglyoxal (MGO), induce C2C12 myotube atrophy as endogenous AGE-derived BSA. ROS production, mitochondrial dysfunction, mitophagy, ubiquitin–proteasome activation, and inhibition of myogenic potential are common atrophying mechanisms used by MGO and AGE-BSA. Although of different origins, ROS are mainly responsible for AGE-induced myotube atrophy. However, while AGE-BSA activates the RAGE-myogenin axis, reduces anabolic mTOR, and causes mitochondrial damage, MGO induces glycolytic stress and STAT3 activation without affecting RAGE expression. Among thirty selected natural compounds, Vaccinium macrocarpon (VM), Camellia sinensis, and chlorophyll showed a surprising ability in counteracting in vitro AGE formation. However, only the standardized VM, containing anti-glycative metabolites as revealed by UHPLC-HRMS analysis, abrogates AGE-induced myotube atrophy. Collectively, our data suggest that WD-linked dAGE consumption predisposes to MW, which might be restricted by VM food supplements. Full article

Cocaine misuse induces microglial activation and neuroinflammation, contributing to neurodegeneration and behavioral impairments. Prior studies have shown that cocaine induces mitochondrial dysfunction, dysregulated mitophagy, and lysosomal impairment in microglia. Here, we investigated the therapeutic potential of N-acetylcysteine (NAC) in mitigating cocaine-induced microglial activation and neuroinflammation. Mouse primary microglial cells (MPMs) were pretreated with NAC (5 mM) for 1 h prior to cocaine exposure (10 µM, 24 h) and analyzed for markers of microglial activation, mitophagy, and lysosomal integrity using Western blot, Seahorse assays, lysosomal pH, and membrane potential measurements. In vivo, C57BL/6N mice received NAC (200 mg/kg, i.p.) 1 h before daily cocaine injections (20 mg/kg, i.p.) for 7 days. Behavioral assays (open field, novel object recognition) and brain biomarker analyses (frontal cortex, hippocampus) were performed. Cocaine exposure elevated CD11b, mitophagy markers (PINK1, PARK, and DLP1), and autophagy proteins (Beclin1, and p62), while impairing mitochondrial and lysosomal functions. NAC pretreatment restored mitochondrial and lysosomal function, reduced reactive oxygen species, and normalized protein expression. In vivo, NAC also alleviated cocaine-induced microglial activation and behavioral deficits. These findings highlight NAC as a promising therapeutic agent to counteract cocaine-mediated neuroinflammation and neurotoxicity. Full article

Background: Metabolic syndrome (MetS) is characterized by chronic inflammation, oxidative stress, and mitochondrial dysfunction. MetS is associated with increased intestinal permeability and dysbiosis. The objective of this study was to investigate the effects of peanut shell extract (PSE) and luteolin (LUT) on the kidneys, colon, and ileum in a MetS-like murine model. Methods: Thirty-six male Slc6a14^y/− mice were divided into four groups: low-fat diet (LFD), high-fat diet (HFD), HFD + 200 mg PSE/kg BW (PSE, p.o.), and HFD + 100 mg LUT/kg BW (LUT, p.o.) for 4 months. Outcome measures included glucose homeostasis, intestinal permeability, gut microbiome composition, and mRNA gene expression of mitochondrial homeostasis and inflammation/oxidative stress in the kidneys, colon, and ileum. Results: HFD resulted in glucose dysregulation with hyperglycemia and insulin resistance. PSE and LUT improved insulin tolerance and beta-cell function. PSE and LUT mitigated HFD-increased serum lipopolysaccharide-binding protein concentration. Perturbations in the gut microbiome were associated with HFD, and PSE or LUT reversed some of these changes. Specifically, Phocaeicola vulgatus was depleted by HFD and reverted by PSE or LUT. Relative to the LFD group, the HFD group (1) upregulated mitochondrial fusion (MFN1, MFN2, OPA1), mitophagy (TLR4, PINK1, LC3B), and inflammation (NFκB, TNFα, IL6), and (2) downregulated mitochondrial fission (FIS1, DRP1), biosynthesis (PGC1α, NRF1, NRF2, TFAM), electron transport chain (complex I), and antioxidant enzyme (SOD1) in the kidneys, colon, and ileum. Conclusions: PSE and LUT reversed such HFD-induced changes in the aforementioned gene expression levels. Full article

Mitochondrial dysfunction is a key driver of neurological disorders due to the brain’s high energy demands and reliance on mitochondrial homeostasis. Despite advances in genetic characterization, the heterogeneity of mitochondrial diseases complicates diagnosis and treatment. Mitochondrial dysfunction spans a broad clinical spectrum, from early-onset encephalopathies to adult neurodegeneration, with phenotypic and genetic variability necessitating integrated models of mitochondrial neuropathology. Mutations in nuclear or mitochondrial DNA disrupt energy production, induce oxidative stress, impair mitophagy and biogenesis, and lead to neuronal degeneration and apoptosis. This narrative review provides a structured synthesis of current knowledge by classifying mitochondrial-related neurological disorders according to disrupted biochemical pathways, in order to clarify links between genetic mutations, metabolic impairments, and clinical phenotypes. More specifically, a pathway-oriented framework was adopted that organizes disorders based on the primary mitochondrial processes affected: oxidative phosphorylation (OXPHOS), pyruvate metabolism, fatty acid β-oxidation, amino acid metabolism, phospholipid remodeling, multi-system interactions, and neurodegeneration with brain iron accumulation. Genetic, clinical and molecular data were analyzed to elucidate shared and distinct pathophysiological features. A comprehensive table synthesizes genetic causes, inheritance patterns, and neurological manifestations across disorders. This approach offers a conceptual framework that connects molecular findings to clinical practice, supporting more precise diagnostic strategies and the development of targeted therapies. Advances in whole-exome sequencing, pharmacogenomic profiling, mitochondrial gene editing, metabolic reprogramming, and replacement therapy—promise individualized therapeutic approaches, although hurdles including heteroplasmy, tissue specificity, and delivery challenges must be overcome. Ongoing molecular research is essential for translating these advances into improved patient care and quality of life. Full article

Postbiotics, which are non-viable microbial derivatives including short-chain fatty acids (SCFAs), microbial peptides, and cell wall components, are emerging as novel therapeutic agents for Inflammatory Bowel Disease (IBD). Unlike probiotics, postbiotics offer a safer, more stable alternative while retaining potent bioactivity. IBD, encompassing Crohn’s disease and ulcerative colitis, is characterized by chronic gastrointestinal inflammation, epithelial barrier dysfunction, and immune dysregulation. Recent evidence links mitochondrial dysfunction marked by impaired energy metabolism, oxidative stress, and apoptosis with the pathogenesis and persistence of IBD. Postbiotics have shown the ability to modulate mitochondrial health through multiple mechanisms. SCFAs such as butyrate serve as primary energy substrates for colonocytes, enhancing mitochondrial respiration and promoting biogenesis. They improve mitochondrial function and boost ATP production. Moreover, postbiotics reduce oxidative damage by regulating antioxidant defenses. These antioxidant actions limit epithelial apoptosis and preserve cellular integrity. In addition, postbiotics regulate mitophagy and help maintain mitochondrial quality and reduce inflammation. Structural components such as lipoteichoic acid and peptidoglycan have been shown to interact with mitochondrial pathways and modulate inflammatory responses. Collectively, this review explores the interplay between mitochondrial dysfunction, IBD, and preventive approach using postbiotics. Understanding the connections with postbiotics could open up new avenues for therapeutic interventions aimed at mitigating IBD severity in people with IBD. Full article

Background: Microplastics (MPs) can be inhaled by people. However, the relationships between long-term exposure to inhaled MPs, pulmonary fibrosis, and mitochondrial dysfunction are not completely clear. Methods: SD rats were exposed to a 0.0125, 0.125, 0.31, or 1.25 mg/day dosage of mixed polystyrene MPs (PS-MPs), with the particle sizes ranging from 500 nm to 4 µm, via intratracheal administration, for 7 to 35 consecutive days. Results: PS-MPs with particle sizes ranging from 1 µm to 4 µm were deposited in the lungs. The contents of NFκB-mediated proinflammatory cytokines were increased in the lungs of the rats after 7 days of PS-MP exposure. After exposure to PS-MPs, the degree of collagen deposition and the expression of TGF-β1/Smad increased significantly, and the levels of phosphorylated Akt (p-Akt) and nuclear β-catenin decreased significantly. The number of healthy mitochondria decreased, the expression of mitochondrial fission and fusion proteins increased, and the level of PINK1/Parkin-mediated mitophagy decreased in the lungs of the rats after 7 days of PS-MP exposure. A benchmark dose (BMD) of 0.151 mg/day and a benchmark dose lower confidence limit (BMDL) of 0.031 mg/day were identified on the basis of the subchronic effects of the intratracheal administration of the PS-MPs. Conclusions: Our study provides an in-depth understanding of the potential impacts of MP pollution on respiratory diseases. Full article

Microglia, the resident immune cells of the central nervous system (CNS), play essential roles in maintaining brain homeostasis. While transient activation is protective, chronic microglial reactivity contributes to neuroinflammatory damage and neurodegeneration. The mitochondrial mechanisms underlying this shift remain poorly understood. Here, we investigated whether lipopolysaccharide (LPS) induces coordinated mitochondrial and metabolic alterations in BV-2 microglial cells. LPS stimulation (100 ng/mL, 24 h) induced a reactive phenotype, with increased Iba1 (+82%), F4/80 (+132%), and Cd68 (+44%), alongside elevated hydrogen peroxide (~6-fold) and nitrite (~45-fold). Cytotoxicity increased by 40% (LDH assay), and cell viability dropped to ~80% of the control (MTT). Extracellular lactate increased, indicating glycolytic reprogramming. However, LPS-primed cells showed greater ATP depletion under antimycin A challenge, reflecting impaired metabolic flexibility. Hoechst staining revealed a ~4-fold increase in pyknotic nuclei, indicating apoptosis. Mitochondrial dysfunction was confirmed by a 30–40% reduction in membrane potential (TMRE, JC-1), a ~30% loss of Tomm20, and changes in dynamics: phospho-Drp1 increased (+23%), while Mfn1/2 decreased (33%). Despite a ~70% rise in Lamp2 signal, Tomm20–Lamp2 colocalization decreased, suggesting impaired mitophagy. High-resolution respirometry revealed decreased basal (−22%), ATP-linked (24%), and spare respiratory capacity (41%), with increased non-mitochondrial oxygen consumption. These findings demonstrate that LPS induces mitochondrial dysfunction, loss of metabolic adaptability, and increased apoptotic susceptibility in microglia. Mitochondrial quality control and energy flexibility emerge as relevant targets to better understand and potentially modulate microglial responses in neuroinflammatory and neurodegenerative conditions. Full article

Mitochondrial integrity is indispensable for pulmonary cellular homeostasis, with its dysfunction increasingly being implicated as a central mechanism in the etiology of respiratory disorders. We present a comprehensive overview of the integral role played by mitochondrial dynamics, such as fusion, fission, mitophagy, intracellular trafficking, and biogenesis, in maintaining pulmonary homeostasis. This study further explores how perturbations in these processes contribute to the pathogenesis of diverse lung disorders, including chronic obstructive pulmonary disease (COPD), bronchopulmonary dysplasia (BPD), pulmonary arterial hypertension (PAH), idiopathic pulmonary fibrosis (IPF), and drug-induced lung disease. It further explores how perturbations in these processes contribute to the pathogenesis of diverse lung disorders—for example, chronic obstructive pulmonary disease (COPD; responsible for roughly 55% of chronic respiratory disease cases), bronchopulmonary dysplasia (BPD; affecting up to 45% of infants born before 29 weeks of gestation), pulmonary arterial hypertension (PAH; a rare condition causing about 22,000 deaths worldwide in 2021), idiopathic pulmonary fibrosis (IPF; 0.33–4.51 cases per 10,000 persons), and drug-induced lung disease. Evidence demonstrates that mitochondria-triggered apoptosis, metabolic shifts, and subsequent inflammatory signaling act together to drive airway tissue remodeling and fibrotic progression across these lung diseases. Furthermore, this review evaluates the therapeutic potential of mitochondrial-targeted drugs, such as MitoQ and SS31, and metformin, which have shown promise in basic and preclinical studies. Preclinical and early clinical evaluations include an ongoing trial of the mitochondrial-targeted antioxidant MitoQ (NCT02966665, phase 1) in COPD, a 4-month open-label DCA study in PAH patients, and studies determining the preclinical efficacy of SS-31 and metformin in IPF models. Ultimately, integrating mitochondrial biomarkers into clinical practice holds the potential not only to facilitate early disease detection but also to enable the development of precision therapies, thereby offering renewed hope for patients afflicted with chronic lung diseases. Full article

Mitochondrial dysfunction is a pivotal driver in the pathogenesis of acute kidney injury (AKI), chronic kidney disease (CKD), and congenital anomalies of the kidney and urinary tract (CAKUT). The kidneys, second only to the heart in mitochondrial density, rely on oxidative phosphorylation to meet the high ATP demands of solute reabsorption and filtration. Disrupted mitochondrial dynamics, such as excessive fission mediated by Drp1, exacerbate tubular apoptosis and inflammation in AKI models like ischemia–reperfusion injury. In CKD, persistent mitochondrial dysfunction drives oxidative stress, fibrosis, and metabolic reprogramming, with epigenetic mechanisms (DNA methylation, histone modifications, non-coding RNAs) regulating genes critical for mitochondrial homeostasis, such as PMPCB and TFAM. Epigenetic dysregulation also impacts mitochondrial–ER crosstalk, influencing calcium signaling and autophagy in renal pathology. Mitophagy, the selective clearance of damaged mitochondria, plays a dual role in kidney disease. While PINK1/Parkin-mediated mitophagy protects against cisplatin-induced AKI by preventing mitochondrial fragmentation and apoptosis, its dysregulation contributes to fibrosis and CKD progression. For instance, macrophage-specific loss of mitophagy regulators like MFN2 amplifies ROS production and fibrotic responses. Conversely, BNIP3/NIX-dependent mitophagy attenuates contrast-induced AKI by suppressing NLRP3 inflammasome activation. In diabetic nephropathy, impaired mitophagy correlates with declining eGFR and interstitial fibrosis, highlighting its diagnostic and therapeutic potential. Emerging therapeutic strategies target mitochondrial dysfunction through antioxidants (e.g., MitoQ, SS-31), mitophagy inducers (e.g., COPT nanoparticles), and mitochondrial transplantation, which mitigates AKI by restoring bioenergetics and modulating inflammatory pathways. Nanotechnology-enhanced drug delivery systems, such as curcumin-loaded nanoparticles, improve renal targeting and reduce oxidative stress. Epigenetic interventions, including PPAR-α agonists and KLF4 modulators, show promise in reversing metabolic reprogramming and fibrosis. These advances underscore mitochondria as central hubs in renal pathophysiology. Tailored interventions—ranging from Drp1 inhibition to mitochondrial transplantation—hold transformative potential to mitigate kidney injury and improve clinical outcomes. Additionally, dietary interventions and novel regulators such as adenogens are emerging as promising strategies to modulate mitochondrial function and attenuate kidney disease progression. Future research should address the gaps in understanding the role of mitophagy in CAKUT and optimize targeted delivery systems for precision therapies. Full article

Mitochondria play a central role in energy metabolism and continuously adapt through dynamic processes such as fusion and fission. When the balance between these processes is disrupted, it can lead to mitochondrial dysfunction and increased oxidative stress, contributing to the development and progression of various cardiometabolic diseases (CMDs). Their role is crucial in diabetes mellitus (DM), since their dysfunction drives β-cell apoptosis, immune activation, and chronic inflammation through excessive ROS production, worsening endogenous insulin secretion. Moreover, sympathetic nervous system activation and altered dynamics, contribute to hypertension through oxidative stress, impaired mitophagy, endothelial dysfunction, and cardiomyocyte hypertrophy. Furthermore, the role of mitochondria is catalytic in endothelial dysfunction through excessive reactive oxygen species (ROS) production, disrupting the vascular tone, permeability, and apoptosis, while impairing antioxidant defense and promoting inflammatory processes. Mitochondrial oxidative stress, resulting from an imbalance between ROS/Reactive nitrogen species (RNS) imbalance, promotes atherosclerotic alterations and oxidative modification of oxidizing low-density lipoprotein (LDL). Mitochondrial DNA (mtDNA), situated in close proximity to the inner mitochondrial membrane where ROS are generated, is particularly susceptible to oxidative damage. ROS activate redox-sensitive inflammatory signaling pathways, notably the nuclear factor kappa B (NF-κB) pathway, leading to the transcriptional upregulation of proinflammatory cytokines, chemokines, and adhesion molecules. This proinflammatory milieu promotes endothelial activation and monocyte recruitment, thereby perpetuating local inflammation and enhancing atherogenesis. Additionally, mitochondrial disruptions in heart failure promote further ischemic injury and excessive oxidative stress release and impair ATP production and Ca²⁺ dysregulation, contributing to cell death, fibrosis, and decreased cardiac performance. This narrative review aims to investigate the intricate relationship between mitochondrial dysfunction and CMDs. Full article

Cold-inducible RNA-binding protein (CIRBP) has been reported to be involved in various cellular functions by regulating programmed cell death (PCD). However, the specific mechanism and function of CIRBP in regulating mitochondrial autophagy are still unclear. In this study, we found that CIRBP induced mitophagy through the AMPK/mTOR pathway to improve the function of yak cumulus cells (YCCs). We observed that low temperatures (32 °C) activated autophagy, increased E2 and P4 secretion, and up-regulated CIRBP expression. CIRBP overexpression activated mitophagy in YCCs, promoted cumulus diffusion, enhanced E2 and P4 synthesis and secretion, and inhibited apoptosis. CIRBP overexpression significantly attenuated the dysfunction of YCCs induced by the inhibition of mitophagy, whereas the activation of mitophagy exerted the same effect as CIRBP overexpression. DOX HCL is an AMPK/mTOR pathway inhibitor. CIRBP overexpression can successfully alleviate the inhibition of mitophagy caused by DOX HCL inhibiting the AMPK/mTOR pathway and can significantly enhance the mitophagy induced by AMPK/mTOR pathway activation in YCCs. Furthermore, we found that the increased expression of CIRBP protein alleviated the apoptosis caused by AKT pathway activation. In summary, CIRBP promoted mitophagy by activating AMPK/mTOR pathway, thereby promoting the synthesis and secretion of steroid hormones and cumulus diffusion in YCCs and enhancing YCCs survival through activating autophagy and AKT signaling pathway, and then improve the function of YCCs. Our research provided new perspectives on CIRBP’s regulation of cell death and highlighted its potential role in female reproductive systems. Full article

Mitochondrial dysfunction is a hallmark of Parkinson’s disease (PD) pathogenesis, contributing to increased oxidative stress and impaired endo-lysosomal-proteasome system efficiency underlying neuronal injury. Genetic studies have identified 19 monogenic mutations—accounting for ~10% of PD cases—that affect mitochondrial function and are associated with early- or late-onset PD. Early-onset forms typically involve genes encoding proteins essential for mitochondrial quality control, including mitophagy and structural maintenance, while late-onset mutations impair mitochondrial dynamics, bioenergetics, and trafficking. Atypical juvenile genetic syndromes also exhibit mitochondrial abnormalities. In idiopathic PD, environmental neurotoxins such as pesticides and MPTP act as mitochondrial inhibitors, disrupting complex I activity and increasing reactive oxygen species. These converging pathways underscore mitochondria as a central node in PD pathology. This review explores the overlapping and distinct mitochondrial mechanisms in genetic and non-genetic PD, emphasizing their role in neuronal vulnerability. Targeting mitochondrial dysfunction finally offers a promising therapeutic avenue to slow or modify disease progression by intervening at a key point of neurodegenerative convergence. Full article