Search Results (107)

Stroke is still considered a predominant cause of morbidity and mortality, for which research on prevention and cure has been sought to prevent neuronal damage after a stroke incident. In this research, we evaluated the protective effects of virgin coconut oil (VCO) using behavioral, morphophysiological, and gene expression parameters using an ischemic stroke surgical rat model using Sprague Dawley (SD) rats. Eight-week-old SD rats were subjected to repeated oral administration (5 mL/kg/day) of either 1% Tween 80 or VCO. For behavioral and morphophysiological parameters, surgery was performed for each group, after which neurological scoring was performed at 4 h, 24 h, 48 h, 5 d, and 10 d. Further, hematological and brain morphology assessment was performed after euthanasia and necropsy of the animals. For gene expression studies, surgery was performed with animals sacrificed at different time points (baseline, before surgery, 4 h, 24 h, and 48 h after surgery) to collect the brain. Results of the study showed that there are differences in the neurological scores between the two treatments 24 h, 48 h, and 5 d after surgery. Brain morphology assessment also showed favorable results for VCO for infarct size, edema, and hypoxic neurons. Gene expression studies also showed positive results with an increase in the relative expression of angiogenin (Ang), angiopoietin (Angpt 1), Parkin, dynamin-related protein 1 (Drp 1), mitofusin 2 (Mfn 2), and mitochondrial rho (Miro) and decreased relative expression of caspase 3, receptor for advanced glycation end-product (Rage), and glyceraldehyde-3-phosphate dehydrogenase (Gapdh). In summary, the current study shows that VCO may have protective effects on the brain after stroke, which may be explained by the results of the gene expression studies. 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

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder, yet effective agents for its prevention and therapy remain highly limited. Epicoccin A, a significant secondary metabolite from Exserohilum sp., demonstrates various biological activities; however, its neuroprotective effects have not been elucidated. Here, we investigated the therapeutic potential of epicoccin A for PD by evaluating its impact on neural phenotype, reactive oxygen species (ROS) generation, and locomotor activity in PD-like zebrafish. Transcriptomic analysis and molecular docking were conducted, with key gene expressions further verified using real-time qPCR. As a result, epicoccin A notably mitigated dopaminergic neuron loss, neural vasculature deficiency, nervous system injury, ROS accumulation, locomotor impairments, and abnormal expressions of hallmark genes associated with PD and oxidative stress. Underlying mechanism investigation indicated epicoccin A may alleviate PD-like symptoms by activating PINK1/Parkin-dependent mitophagy, as evidenced by the reversal of aberrant gene expressions related to the pink1/parkin pathway and its upstream mTOR/FoxO pathway following epicoccin A co-treatments. This finding was further confirmed by the robust interactions between epicoccin A and these mitophagy regulators. Our results suggest that epicoccin A relieves PD symptoms by activating pink1/parkin-dependent mitophagy and inhibiting excessive oxidative stress, highlighting its potential as a therapeutic approach for PD. Full article

Parkinson’s disease (PD), a prevalent neurodegenerative disorder, demonstrates the critical involvement of endoplasmic reticulum stress (ERS) in its pathogenesis. This review comprehensively examines the role and molecular mechanisms of ERS in PD. ERS represents a cellular stress response triggered by imbalances in endoplasmic reticulum (ER) homeostasis, induced by factors such as hypoxia and misfolded protein aggregation, which activate the unfolded protein response (UPR) through the inositol-requiring enzyme 1 (IRE1), protein kinase R-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) pathways. Clinical, animal model, and cellular studies have consistently demonstrated a strong association between PD and ERS. Abnormal expression of ERS-related molecules in PD patients’ brains and cerebrospinal fluid (CSF) correlates with disease progression. In animal models (e.g., Drosophila and mice), ERS inhibition alleviates dopaminergic neuronal damage. Cellular experiments reveal that PD-mimicking pathological conditions induce ERS, while interactions between ERS and mitochondrial dysfunction promote neuronal apoptosis. Mechanistically, (1) pathological aggregation of α-synuclein (α-syn) and ERS mutually reinforce dopaminergic neuron damage; (2) leucine-rich repeat kinase 2 (LRRK2) gene mutations induce ERS through thrombospondin-1 (THBS1)/transforming growth factor beta 1 (TGF-β1) interactions; (3) molecules such as Parkin and PTEN-induced kinase 1 (PINK1) regulate ERS in PD. Furthermore, ERS interacts with mitochondrial dysfunction, oxidative stress, and neuroinflammation to exacerbate neuronal injury. Emerging therapeutic strategies show significant potential, including artificial intelligence (AI)-assisted drug design targeting ERS pathways and precision medicine approaches exploring non-pharmacological interventions such as personalized electroacupuncture. Future research should focus on elucidating ERS-related mechanisms and identifying novel therapeutic targets to develop more effective treatments for PD patients, ultimately improving their quality of life. Full article

Background/Objectives: Parkinson’s disease (PD) is a rapidly growing neurological disorder in the developed world, affecting millions over the age of 60. The decline in motor functions occurs due to a progressive loss of midbrain dopaminergic neurons, resulting in lowered dopamine levels and impaired muscle function. Studies show defective mitochondrial autophagy (or “mitophagy”) links to PD. Rho-associated coiled-coil containing protein kinases (ROCK) 1 and ROCK2 are serine/threonine kinases, and their inhibition can enhance neuroprotection in PD by promoting mitophagy. Methods: We examine the effects of ROCK inhibitor SR3677, delivered via macrophage-derived small extracellular vesicles (sEVs) to Parkin Q311X(A) PD mouse models. sEVs with SR3677, administered intranasally, increased mitophagy gene expression, reduced inflammatory factors, and elevated dopamine levels in brain tissues. Results: ROCK2 expression decreased, showing the drug’s inhibitory effect. sEV-SR3677 treatment was more effective than treatment with the drug alone, although sham EVs showed lower effects. This suggests that EV-SR3677 not only activates mitochondrial processes but also promotes the degradation of damaged mitochondria through autophagy. Mitochondrial functional assays and oxygen consumption in ex vivo glial cultures revealed that sEV-SR3677 significantly improved mitochondrial respiration compared to that in untreated or SR3677-only treated cells. Conclusion: We demonstrated the efficacy of ROCK2 inhibition on mitochondrial function via sEV-SR3677 in the PD mouse model, necessitating further studies to explore design challenges and mechanisms of sEV-SR3677 as mitochondria-targeted therapy for PD Full article

Neonatal encephalopathy suspected to be due to hypoxic ischaemic encephalopathy (NESHIE) carries the risk of death or severe disability (cognitive defects and cerebral palsy). Previous genetic studies on NESHIE have predominantly focused on exomes or targeted genes. The objective of this study was to identify genetic variants associated with moderate–severe NESHIE through whole-genome, unbiased analysis. Variant filtering and prioritization were performed, followed by association testing both on a case–control basis and to compare the grades of severity and/or progression. Association testing on neonates with NESHIE (N = 172) and ancestry-matched controls (N = 288) produced 71 significant genetic variants (false discovery rate corrected p-value < 6.2 × 10⁻⁴), all located in non-coding regions and not previously implicated in NESHIE. Disease-associated variants in non-coding regions are considered to affect regulatory functions, possibly by modifying gene expression, promoters, enhancers, or DNA structure. The most significant variant was at position 6:162010973 in the Parkin RBR E3 ubiquitin protein ligase (PRKN) intron. Intronic variants were also identified in genes involved in inflammatory processes (SLCO3A1), DNA repair (ZGRF1), synaptogenesis (CNTN5), haematopoiesis (ASXL2), and the transcriptional response to hypoxia (PADI4). Ten variants were associated with a higher severity or lack of improvement in NESHIE, including one in ADAMTS3, which encodes a procollagen amino protease with a role in angiogenesis and lymphangiogenesis. This analysis represents one of the first efforts to analyze whole-genome data to investigate the genetic complexity of NESHIE in diverse ethnolinguistic groups of African origin and provides direction for further study. Full article

Metabolic cardiomyopathy, encompassing diabetic and obese cardiomyopathy, is an escalating global health concern, driven by the rising prevalence of metabolic disorders such as insulin resistance, type 1 and type 2 diabetes, and obesity. These conditions induce structural and functional alterations in the heart, including left ventricular dysfunction, fibrosis, and ultimately heart failure, particularly in the presence of coronary artery disease or hypertension. Autophagy, a critical cellular process for maintaining cardiac homeostasis, is frequently disrupted in metabolic cardiomyopathy. This review explores the role of autophagy in the pathogenesis of high-fat diet (HFD) and streptozotocin (STZ)-induced metabolic cardiomyopathy, focusing on non-selective and selective autophagy pathways, including mitophagy, ER-phagy, and ferritinophagy. Key proteins and genes such as PINK1, Parkin, ULK1, AMPK, mTOR, ATG7, ATG5, Beclin-1, and miR-34a are central to the regulation of autophagy in metabolic cardiomyopathy. Dysregulated autophagic flux impairs mitochondrial function, promotes oxidative stress, and drives fibrosis in the heart. Additionally, selective autophagy processes such as lipophagy, regulated by PNPLA8, and ferritinophagy, modulated by NCOA4, play pivotal roles in lipid metabolism and iron homeostasis. Emerging therapeutic strategies targeting autophagy, including plant extracts (e.g., curcumin, dihydromyricetin), endogenous compounds (e.g., sirtuin 3, LC3), and lipid/glucose-lowering drugs, offer promising avenues for mitigating the effects of metabolic cardiomyopathy. Despite recent advances, the precise mechanisms underlying autophagy in this context remain poorly understood. A deeper understanding of autophagy’s regulatory networks, particularly involving these critical genes and proteins, may lead to novel therapeutic approaches for treating metabolic cardiomyopathy. Full article

Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world. Currently, PD is incurable, and the diagnosis of PD mainly relies on clinical manifestations. The central pathological event in PD is the abnormal aggregation and deposition of misfolded α-synuclein (α-Syn) protein aggregates in the Lewy body (LB) in affected brain areas. Behaving as a prion-like seeding, the misfolded α-syn protein can induce and facilitate the aggregation of native unfolded α-Syn protein to aggravate α-Syn protein aggregation, leading to PD progression. Recently, in a blood-based α-Syn seeding amplification assay (SAA), Kluge et al. identified pathological α-Syn seeding activity in PD patients with Parkin (PRKN) gene variants. Additionally, pathological α-syn seeding activity was also identified in sporadic PD and PD patients with Leucine-rich repeat kinase 2 (LRRK2) or glucocerebrosidase (GBA) gene variants. Principally, the α-Syn SAA can be used to detect pathological α-Syn seeding activity, which will significantly enhance PD diagnosis, progression monitoring, prognosis prediction, and anti-PD therapy. The significance and future strategies of α-Syn SAA protocol are highlighted and proposed, whereas challenges and limitations of the assay are discussed. Full article

As the global population ages, the rising prevalence of neurodegenerative diseases, characterized by abnormal protein aggregates, presents significant challenges for early diagnosis and disease monitoring. Identifying accessible tissue biomarkers is crucial for advancing our ability to detect and track the progression of these diseases. Among the most promising biomarkers is the skin, which shares a common embryological origin with the brain and central nervous system (CNS). This biological connection positions the skin as a potential reflection of CNS pathology. Over the past decades, gene expression studies have demonstrated that key genes involved in neurodegenerative diseases are also expressed in skin tissues. Genes such as APP, PSEN1, PPA2, PINK1, LRRK2, PLCB4, MAPT, SPAST, and SPG7 are prominent in this regard. Beyond gene expression, proteins related to neurodegenerative diseases—such as α-synuclein, TAU, PARKIN, and prion protein (PrP)—have been isolated from the skin of affected individuals, underscoring the skin’s capacity to mirror neural degeneration. This non-invasive window into neurodegenerative processes is further enhanced by advances in stem cell technology, which have allowed for the generation of human-induced pluripotent stem cells (iPSCs) from patient-derived fibroblasts. These iPSCs offer a valuable model for studying disease mechanisms and developing therapeutic approaches. This review conducts a comprehensive analysis of the literature from databases such as PubMed, Google Scholar, and ResearchGate, emphasizing the unique potential of the skin as a non-invasive biomarker for neurodegenerative diseases. It explores how the skin serves as a bridge between gene expression and disease pathology in both the skin and the CNS. By leveraging this biological connection, the skin emerges as a promising model for enhancing our understanding of neurodegenerative disorders and developing innovative strategies for early detection and treatment. However, significant limitations remain, requiring further validation to establish the specificity and sensitivity of these biomarkers. Full article

Mitochondria is an important organelle for the oocyte-to-embryo transition in the early embryonic development period. The oocyte uses mitochondria functionally and its mitochondrial DNA (mtDNA) content as the main energy source in the embryo development at the preimplantation stage. The aim of this study is to compare mitophagic, apoptotic and humanin gene expressions from the culture medium fluid in which embryos are developed and monitored among normoresponder (NOR), polycystic ovary syndrome (PCOS), young and older patients with poor ovarian reserve (POR). The study groups consisted of infertile patients who applied to the Bahçeci Umut IVF Center as NOR (Control), PCOS, POR-Advanced (POR-A) and POR-Young (POR-Y). After the isolation of total RNA from the collected samples, MFN1, MFN2, PINK1, PARKIN, SMN1, SMN2, p53 and Humanin gene expressions were determined by Real Time-PCR. The average age of only the POR-A was determined to be higher than the NOR (p < 0.001). The MFN1, SMN2 (p < 0.05), Humanin and p53 gene expressions (p < 0.001) increased, while PINK1 gene expression decreased (p < 0.05), in the POR-Y compared to the NOR. A decrease in MFN2, PARKIN (p < 0.05) and PINK1 gene expressions was determined in the PCOS compared to the NOR (p < 0.001). Furthermore, a decrease was observed in MFN2, PINK1 (p < 0.001) and Humanin gene expressions compared to the NOR (p < 0.05). The current data are the first in the literature determining the apoptotic and mitophagic status of the oocyte. The current results prove that waste embryo culture fluid may provide a non-invasive profile for important cellular parameters such as mitochondrial dysfunction in female infertility. The evaluation of significant cellular parameters can be performed much earlier without any intervention into the embryo. Full article

Mutations in the parkin gene product Parkin give rise to autosomal recessive juvenile parkinsonism. Parkin is an E3 ubiquitin ligase that is a critical participant in the process of mitophagy. Parkin has a complex structure that integrates several allosteric signals to maintain precise control of its catalytic activity. Though its allosterically controlled structural reorganization has been extensively characterized by crystallography, the energetics and mechanisms of allosteric regulation of Parkin are much less well understood. Allostery is fundamentally linked to the energetics of the cooperative (sub)structure of the protein. Herein, we examine the mechanism of allosteric activation by phosphorylated ubiquitin binding to the enzymatic core of Parkin, which lacks the antagonistic Ubl domain. In this way, the allosteric effects of the agonist phosphorylated ubiquitin can be isolated. Using native-state hydrogen exchange monitored by mass spectrometry, we find that the five structural domains of the core of Parkin are energetically distinct. Nevertheless, association of phosphorylated ubiquitin destabilizes structural elements that bind the ubiquitin-like domain antagonist while promoting the dissociation of the catalytic domain and energetically poises the protein for transition to the fully activated structure. Full article

Introduction: Mitophagy, the selective degradation of damaged mitochondria, is essential for maintaining cellular health and function, particularly in high-energy demanding post-mitotic cells like neurons and in microglial cells. Aging results in impaired mitophagy, leading to mitochondrial dysfunction, oxidative stress, the release of damage-associated proteins (DAMPs), and neuroinflammation, which contribute to neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Mitochondrial dysfunction also contributes to the pathophysiology of depression by affecting synaptic plasticity, increasing neuroinflammation, and heightening oxidative stress. Aim: In this review, we summarize the recent developments on mechanisms of mitophagy, its therapeutic role in neuroprotection, and its implications in aging and neuroinflammation, complemented by future research requirements and implications. Result/Discussion: Therapeutic strategies that promote mitochondrial health, including enhancing mitophagy and mitochondrial biogenesis, show promise in treating neurodegenerative diseases and depression. Recent findings have emphasized therapeutic strategies to modulate mitophagy, such as pharmacological agents like urolithin A and rapamycin, genetic interventions such as PINK1/Parkin gene therapy, mitochondrial transplantation, and lifestyle and dietary interventions such as caloric restriction, exercise, and dietary supplements such as resveratrol and CoQ10. Key regulators of mitophagy, including the PINK1/Parkin pathway and various proteins like BNIP3, NIX, and FUNDC1, which facilitate the removal of damaged mitochondria, play a crucial role. Conclusions: These results highlight the importance of understanding the interplay between mitophagy and neuroinflammation and show that modulation of mitophagy can reduce oxidative stress and improve neuroinflammatory outcomes and depression in age-related neurodegenerative diseases. However, despite significant progress, challenges remain in understanding the underlying molecular mechanisms of mitophagy and its therapeutic regulation in aging disorders. Full article

Neuroinflammation is considered to be one of the driving factors in Parkinson’s disease (PD). This study was conducted using neuronal and glial cell cultures differentiated from induced pluripotent stem cells (iPSC) of healthy donors (HD) and PD patients with different PARK2 mutations (PD). Based on the results of RNA sequencing, qPCR and ELISA, we revealed transcriptional and post-transcriptional changes in HD and PD neurons cultivated in HD and PD glial-conditioned medium. We demonstrated that if one or both of the components of the system, neurons or glia, is Parkin-deficient, the interaction resulted in the down-regulation of a number of key genes related to inflammatory intracellular pathways and negative regulation of apoptosis in neurons, which might be neuroprotective. In PD neurons, the stress-induced up-regulation of APLNR was significantly stronger compared to HD neurons and was diminished by glial soluble factors, both HD and PD. PD neurons in PD glial conditioned medium increased APLN expression and also up-regulated apelin synthesis and release into intracellular fluid, which represented another compensatory action. Overall, the reported results indicate that neuronal self-defense mechanisms contribute to cell survival, which might be characteristic of PD patients with Parkin-deficiency. Full article

Parkinson’s disease (PD) is a multifactorial, chronic, and progressive neurodegenerative disorder inducing movement alterations as a result of the loss of dopaminergic (DAergic) neurons of the pars compacta in the substantia nigra and protein aggregates of alpha synuclein (α-Syn). Although its etiopathology agent has not yet been clearly established, environmental and genetic factors have been suggested as the major contributors to the disease. Mutations in the glucosidase beta acid 1 (GBA1) gene, which encodes the lysosomal glucosylceramidase (GCase) enzyme, are one of the major genetic risks for PD. We found that the GBA1 K198E fibroblasts but not WT fibroblasts showed reduced catalytic activity of heterozygous mutant GCase by −70% but its expression levels increased by 3.68-fold; increased the acidification of autophagy vacuoles (e.g., autophagosomes, lysosomes, and autolysosomes) by +1600%; augmented the expression of autophagosome protein Beclin-1 (+133%) and LC3-II (+750%), and lysosomal–autophagosome fusion protein LAMP-2 (+107%); increased the accumulation of lysosomes (+400%); decreased the mitochondrial membrane potential (∆Ψm) by −19% but the expression of Parkin protein remained unperturbed; increased the oxidized DJ-1Cys106-SOH by +900%, as evidence of oxidative stress; increased phosphorylated LRRK2 at Ser935 (+1050%) along with phosphorylated α-synuclein (α-Syn) at pathological residue Ser129 (+1200%); increased the executer apoptotic protein caspase 3 (cleaved caspase 3) by +733%. Although exposure of WT fibroblasts to environmental neutoxin rotenone (ROT, 1 μM) exacerbated the autophagy–lysosomal system, oxidative stress, and apoptosis markers, ROT moderately increased those markers in GBA1 K198E fibroblasts. We concluded that the K198E mutation endogenously primes skin fibroblasts toward autophagy dysfunction, OS, and apoptosis. Our findings suggest that the GBA1 K198E fibroblasts are biochemically and molecularly equivalent to the response of WT GBA1 fibroblasts exposed to ROT. Full article

Alzheimer’s disease (AD) is a neurodegenerative disease. Mitochondrial energy metabolism and p70 ribosomal protein S6 kinase (p70S6K) play significant roles in AD pathology. However, the potential relationship between them is unclear. In this study, bioinformatics methods were initially applied to analyze the transcriptomic data in the CA1 and the primary visual cortex of patients with AD and Aβ42-treated SH-SY5Y cells. By applying secreted Aβ42 and p70S6K gene silencing in cells, we explored disorders in mitochondrial function and the regulatory roles of p70S6K by flow cytometry, laser scanning confocal microscopy, high-performance liquid chromatography, Western blotting, and quantitative reverse transcription PCR. The study reveals that impaired mitochondrial energy metabolism is a potential pathological feature of AD and that p70S6K gene silencing reversed most of the changes induced by Aβ42, such as the activities of the electron transport chain complexes I and III, as well as ATP synthase, ATP production, generation of reactive oxygen species, mitochondrial membrane potential, and phosphorylation of AMPK, PINK1, and Parkin, all of which are required for mitochondria to function properly in the cell. Full article