bims-mistre 2025-03-23 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–03–23
twelve papers selected by
Ellen Siobhan Mitchell, MitoQ

The neuroprotective role of Humanin in Alzheimer's disease: The molecular effects.
Oxidative Stress and the Role of Immune Cells in Alzheimer's Disease: Therapeutic Implications and Future Perspectives.
Thiosulphate sulfurtransferase: Biological roles and therapeutic potential.
Microbiota, mitochondria, and epigenetics in health and disease: converging pathways to solve the puzzle.
CKMT1 deficiency contributes to mitochondrial dysfunction and promotes intestinal epithelial cell apoptosis via reverse electron transfer-derived ROS in colitis.
GPR30-driven fatty acid oxidation targeted by ginsenoside Rd maintains mitochondrial redox homeostasis to restore vascular barrier in diabetic retinopathy.
Mitochondrial quality control in cardiomyocytes: safeguarding the heart against disease and ageing.
Improvement of Glucose Metabolism by Pennogenin 3-O-β-Chacotrioside via Activation of IRS/PI3K/Akt Signaling and Mitochondrial Respiration in Insulin-Resistant Hepatocytes.
Highly spatial-temporal electrochemical profiling of molecules trafficking at a single mitochondrion in one living cell.
An Updated Review on the Complex Association of Cardiovascular Disease (CVD) and Depression.
Astaxanthin: a nature's versatile compound utilized for diverse applications and its therapeutic effects.
The Mitochondrial Targeting Drug SkQ1 Attenuates the Progression of Post- Traumatic Osteoarthritis through Suppression of Mitochondrial Oxidative Stress.

Eur J Pharmacol. 2025 Mar 14. pii: S0014-2999(25)00264-X. [Epub ahead of print]998 177510

The neuroprotective role of Humanin in Alzheimer's disease: The molecular effects.

Saad Misfer Alqahtani, Hayder M Al-Kuraishy, Ali I Al-Gareeb, Athanasios Alexiou, Mohamed N Fawzy, Marios Papadakis, Basant M Al-Botaty, Mubarak Alruwaili, Gaber El-Saber Batiha.

  Humanin (HN) is an endogenous micropeptide also known as a mitochondria-derived peptide. It has a neuroprotective effect against Alzheimer's disease (AD) and other neurodegenerative diseases by improving hippocampal acetylcholine and attenuating the development of oxidative stress and associated neurotoxicity. HN protects the neuron from the toxic effects of amyloid beta (Aβ). HN is regarded as a biomarker of mitochondrial stress. Interestingly, aging reduces brain expression of HN, leading to cognitive impairment and elevating the risk of neurodegeneration, including AD. However, in old subjects and AD patients, circulating HN levels increase as a compensatory mechanism to reduce neurodegeneration and mitochondrial dysfunction in AD. Conversely, other studies demonstrated a reduction in circulating HN levels in AD. These findings indicated controversial points regarding the precise mechanistic role of HN in AD. Therefore, the aim of this review was to discuss the exact role of HN in AD neuropathology and also to discuss the molecular mechanisms of HN in AD.

Keywords:  Alzheimer's disease; Humanin; Mitochondria-derived peptide; Neuropathology; Oxidative stress; Trimeric receptor

DOI:  https://doi.org/10.1016/j.ejphar.2025.177510
CNS Neurol Disord Drug Targets. 2025 Mar 20.

Oxidative Stress and the Role of Immune Cells in Alzheimer's Disease: Therapeutic Implications and Future Perspectives.

Nidhi Puranik, Minseok Song.

  The most common neurodegenerative illness and leading cause of death in the world is Alzheimer's disease (AD), which is extremely expensive to treat. None of the AD treatments that are currently in the market with approval have any effect on disease progression. However, numerous clinical studies aimed at reducing amyloid beta (Aβ) plaque development, boosting Aβ clearance, or reducing neurofibrillary tangle (NFT) failed or had conflicting results. As oxidative stress (OS), mitochondrial dysfunction, and chronic neuroinflammation are implicated in numerous interconnected vicious cascades, research has revealed new therapeutic targets, including enhancing mitochondrial bioenergetics and quality control, reducing oxidative stress, or modulating neuroinflammatory pathways. This review examines the role of oxidative stress (OS), mitochondrial dysfunction, neuroinflammation, and the interplay between peripheral and central immune systems in the pathogenesis of AD. We highlight how OS and immune dysregulation drive chronic neuroinflammation, exacerbating AD progression. Immune cells and inflammatory molecules emerge as critical players in disease pathology. Overall, this review concludes that targeting OS and immune system crosstalk represents promising therapeutic strategies for mitigating AD progression, providing a foundation for future interventions.

Keywords:  Alzheimer’s disease; Neuroinflammation; immune cells.; interleukins; microglia; oxidative stress; therapeutic targets

DOI:  https://doi.org/10.2174/0118715273355336250226055826
Redox Biol. 2025 Mar 14. pii: S2213-2317(25)00108-9. [Epub ahead of print]82 103595

Thiosulphate sulfurtransferase: Biological roles and therapeutic potential.

Yang Luo, Shaden Melhem, Martin Feelisch, Laurent Chatre, Nicholas M Morton, Amalia M Dolga, Harry van Goor.

  Mitochondria are central to eukaryotic cell function, driving energy production, intermediary metabolism, and cellular homeostasis. Dysregulation of mitochondrial function often results in oxidative stress, a hallmark of numerous diseases, underscoring the critical need for maintaining mitochondrial integrity. Among mitochondrial enzymes, thiosulfate sulfurtransferase (TST) has emerged as a key regulator of sulfur metabolism, redox balance, and Fe-S protein maintenance. Beyond its well-known role in cyanide detoxification, TST facilitates hydrogen sulfide (H2S) metabolism by catalyzing the transfer of sulfur from persulfides (R-SSH) to thiosulfate (S2O32-), promoting H2S oxidation and preventing its toxic accumulation. Additionally, TST contributes to the thiol-dependent antioxidant system by regulating reactive sulfur species and sustaining mitochondrial functionality through its role in sulfide-driven bioenergetics. This review highlights the biochemical and therapeutic significance of TST in mitochondrial and cellular health, emphasizing its protective roles in diseases associated with oxidative stress and mitochondrial dysfunction. Dysregulation of TST has been implicated in diverse pathologies, including specific metabolic disorders, neurological diseases, cardiovascular conditions, kidney dysfunction, inflammatory bowel disease, and cancer. These associations underline TST's potential as a biomarker and therapeutic target. Therapeutic strategies to activate the TST pathway are explored, with a focus on sodium thiosulfate (STS), novel small molecule (Hit 2), and recombinant hTST protein. STS, an FDA-approved compound, has demonstrated antioxidant and anti-inflammatory effects across multiple preclinical models, mitigating oxidative damage and improving mitochondrial integrity. A slow-release oral formulation of STS is under development, offering promise for expanding its clinical applications. Small molecule activators like Hit 2 and hTST protein have shown efficacy in enhancing mitochondrial respiration and reducing oxidative stress, though both reagents need further in vitro and in vivo investigations. Despite promising advancements, TST-based therapies remain underexplored. Future research should focus on leveraging TST's interplay with pathways like NRF2 signaling, investigating its broader protective roles in cellular health, and developing targeted interventions. Enhancing TST activity represents an innovative therapeutic approach for addressing mitochondrial dysfunction, oxidative stress, and their associated pathologies, offering new hope for the treatment of diseases associated with mitochondrial dysfunction.

Keywords:  Mitochondrial dysfunction; Oxidative stress; Redox signaling; Thiosulfate sulfurtransferase (TST)

DOI:  https://doi.org/10.1016/j.redox.2025.103595
Pflugers Arch. 2025 Mar 20.

Microbiota, mitochondria, and epigenetics in health and disease: converging pathways to solve the puzzle.

Natalia Lucia Rukavina Mikusic, Paula Denise Prince, Marcelo Roberto Choi, Luiz Gustavo A Chuffa, Vinícius Augusto Simão, Claudia Castro, Walter Manucha, Isabel Quesada.

  Dysbiosis, which refers to an imbalance in the composition of the gut microbiome, has been associated with a range of metabolic disorders, including type 2 diabetes, obesity, and metabolic syndrome. Although the exact mechanisms connecting gut dysbiosis to these conditions are not fully understood, various lines of evidence strongly suggest a substantial role for the interaction between the gut microbiome, mitochondria, and epigenetics. Current studies suggest that the gut microbiome has the potential to affect mitochondrial function and biogenesis through the production of metabolites. A well-balanced microbiota plays a pivotal role in supporting normal mitochondrial and cellular functions by providing metabolites that are essential for mitochondrial bioenergetics and signaling pathways. Conversely, in the context of illnesses, an unbalanced microbiota can impact mitochondrial function, leading to increased aerobic glycolysis, reduced oxidative phosphorylation and fatty acid oxidation, alterations in mitochondrial membrane permeability, and heightened resistance to cellular apoptosis. Mitochondrial activity can also influence the composition and function of the gut microbiota. Because of the intricate interplay between nuclear and mitochondrial communication, the nuclear epigenome can regulate mitochondrial function, and conversely, mitochondria can produce metabolic signals that initiate epigenetic changes within the nucleus. Given the epigenetic modifications triggered by metabolic signals from mitochondria in response to stress or damage, targeting an imbalanced microbiota through interventions could offer a promising strategy to alleviate the epigenetic alterations arising from disrupted mitochondrial signaling.

Keywords:  Epigenetics; Metabolic syndrome; Microbiota; Mitochondria

DOI:  https://doi.org/10.1007/s00424-025-03072-w
Cell Death Dis. 2025 Mar 15. 16(1): 177

CKMT1 deficiency contributes to mitochondrial dysfunction and promotes intestinal epithelial cell apoptosis via reverse electron transfer-derived ROS in colitis.

Zhijie Wang, Haicong Wu, Xin Chang, Yihang Song, Yan Chen, Ziwei Yan, Lun Gu, Ruxi Pang, Tian Xia, Zixuan He, Zhaoshen Li, Shuling Wang, Yu Bai.

Mitochondrial dysfunction contributes to the pathogenesis of ulcerative colitis (UC). As a mitochondrial isozyme of creatine kinases, which control energy metabolism, CKMT1 is thought to be a critical molecule in biological processes. However, the specific role of CKMT1 in intestinal inflammation remains largely unknown. Here, we observed markedly decreased CKMT1 expression in the colon tissues of UC patients and dextran sodium sulfate (DSS)-induced colitis mice. We generated intestinal epithelial-specific CKMT1 knockout mice and demonstrated the key role of CKMT1 in mitochondrial homeostasis, intestinal epithelial barrier function, oxidative stress, and apoptosis. In the in vitro experiments, CKMT1 expression limited the activation of the intrinsic and extrinsic apoptotic pathways in IECs. Mechanistically, the loss of CKMT1 expression in IECs increased TNF-α-induced mitochondrial reactive oxygen species (ROS) generation via reverse electron transfer (RET). RET-ROS promoted mitochondrial permeability transition pore (mPTP) opening, ultimately resulting in cell apoptosis during intestinal inflammation. In conclusion, our data demonstrated that CKMT1 is important in maintaining intestinal homeostasis and mitochondrial function. This study provides a promising basis for future research and a potential therapeutic target for inflammatory bowel disease (IBD).

DOI: https://doi.org/10.1038/s41419-025-07504-4
Cardiovasc Diabetol. 2025 Mar 14. 24(1): 121

GPR30-driven fatty acid oxidation targeted by ginsenoside Rd maintains mitochondrial redox homeostasis to restore vascular barrier in diabetic retinopathy.

Kai Tang, Congcong Huang, Zhengjie Huang, Zhen Wang, Ninghua Tan.

  Blood-retinal barrier (BRB) breakdown, a pivotal contributor to multiple retinal vascular diseases, manifests as a progressive increase in vascular permeability induced by various pathological stimuli. The functional plasticity of retinal endothelial cells can be intricately shaped by metabolic alteration. However, little is known about the mechanisms through which endothelial metabolic disorders trigger the dissolution of inter-vascular junctions and the selective approaches to targeting metabolic homeostasis. Herein, we identify AMPK-associated fatty acid oxidation (FAO) inhibition as a critical driver of vascular barrier dysfunction via exacerbating redox imbalance. Pharmacological facilitation of FAO by ginsenoside Rd (Rd) suppresses BRB collapse and other secondary retinal damage in diabetic retinopathy (DR). Mechanistically, Rd targets GPR30 to phosphorylate AMPK via the PKA-LKB1-AMPK kinase cascade. The AMPK activation induced by Rd revitalizes hyperglycemia-compromised FAO, and then sustains mitochondrial NADPH regeneration by emphasis on IDH2 at various levels, including substrate supply, transcription, and post-translational modifications. Therefore, Rd alleviates the disruption of BRB integrity driven by mitochondrial oxidative stress, with the vasculoprotection of Rd diminished by GPR30 knockdown and pharmacological attenuation of AMPK. These findings collectively reveal the previously-unanticipated role of endothelial FAO in heightened retinal vascular leakage, and highlight the potential translational application of GPR30 agonism with Rd to mitigate barrier dysfunction, providing a metabolic regulatory therapeutic strategy for DR.

Keywords:  Blood-retinal barrier; Diabetic retinopathy; Fatty acid oxidation; GPR30; Ginsenoside Rd; Mitochondrial oxidative stress

DOI:  https://doi.org/10.1186/s12933-025-02638-3
Nat Rev Cardiol. 2025 Mar 20.

Mitochondrial quality control in cardiomyocytes: safeguarding the heart against disease and ageing.

Rishith Ravindran, Åsa B Gustafsson.

Mitochondria are multifunctional organelles that are important for many different cellular processes, including energy production and biosynthesis of fatty acids, haem and iron-sulfur clusters. Mitochondrial dysfunction leads to a disruption in these processes, the generation of excessive reactive oxygen species, and the activation of inflammatory and cell death pathways. The consequences of mitochondrial dysfunction are particularly harmful in energy-demanding organs such as the heart. Loss of terminally differentiated cardiomyocytes leads to cardiac remodelling and a reduced ability to sustain contraction. Therefore, cardiomyocytes rely on multilayered mitochondrial quality control mechanisms to maintain a healthy population of mitochondria. Mitochondrial chaperones protect against protein misfolding and aggregation, and resident proteases eliminate damaged proteins through proteolysis. Irreparably damaged mitochondria can also be degraded through mitochondrial autophagy (mitophagy) or ejected from cells inside vesicles. The accumulation of dysfunctional mitochondria in cardiomyocytes is a hallmark of ageing and cardiovascular disease. This accumulation is driven by impaired mitochondrial quality control mechanisms and contributes to the development of heart failure. Therefore, there is a strong interest in developing therapies that directly target mitochondrial quality control in cardiomyocytes. In this Review, we discuss the current knowledge of the mechanisms involved in regulating mitochondrial quality in cardiomyocytes, how these pathways are altered with age and in disease, and the therapeutic potential of targeting mitochondrial quality control pathways in cardiovascular disease.

DOI: https://doi.org/10.1038/s41569-025-01142-1
Mol Nutr Food Res. 2025 Mar 19. e70010

Improvement of Glucose Metabolism by Pennogenin 3-O-β-Chacotrioside via Activation of IRS/PI3K/Akt Signaling and Mitochondrial Respiration in Insulin-Resistant Hepatocytes.

Jae-In Lee, Hee Min Lee, Jae-Ho Park, Yu Geon Lee.

   SCOPE: Insulin resistance (IR), which causes chronic hyperglycemia, has been one of the most prevalent components of metabolic syndrome over the centuries. Pennogenin 3-O-β-chacotrioside (P3C), the main steroid glycoside derived from Paris polyphylla, has been found to exert various biological activities. However, the exact role of P3C on glucose metabolism in the IR state remains unexplored.
METHODS AND RESULTS: To induce IR, AML12 cells were exposed to glucose (27 mM) and insulin (10 µg/mL) and then incubated with P3C (0.25 or 0.5 µM) for 24 h. The effects of P3C on glucose metabolism in insulin-resistant AML12 cells were evaluated through glucose consumption assays, real-time quantitative polymerase chain reaction (qPCR), Western blotting, and metabolic analysis for extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Our data showed that P3C significantly improved insulin sensitivity in AML12 hepatocytes with high glucose-induced IR. P3C stimulated insulin sensitivity and glucose uptake by activating the IRS/PI3K/Akt signaling pathway, which enhances glycogen synthesis and suppresses gluconeogenesis in insulin-resistant AML12 cells. In addition, P3C treatment increased the protein expression of p-AMPK and PGC1α, as well as the expression of oxidative phosphorylation complex proteins, potentially enhancing mitochondrial oxidative respiration.
CONCLUSIONS: Our findings imply that P3C could be a therapeutic option for improving metabolic abnormalities associated with IR.

Keywords:  glucose metabolism; hepatocytes; insulin resistance; mitochondria respiration; steroid glycoside

DOI:  https://doi.org/10.1002/mnfr.70010
Proc Natl Acad Sci U S A. 2025 Mar 25. 122(12): e2424591122

Highly spatial-temporal electrochemical profiling of molecules trafficking at a single mitochondrion in one living cell.

Kang Liu, Lina Wu, Yuanyuan Ma, Desheng Chen, Rujia Liu, Xiaobo Zhang, Dechen Jiang, Rongrong Pan.

  Simultaneous profiling of multiple molecules trafficking at a single organelle and the surrounding cytosol within a living cell is crucial for elucidating their functions, necessitating advanced techniques that provide high spatial-temporal resolution and molecule specificity. In this study, we present an electrochemical nanodevice based on a θ-nanopipette designed to coanalyze calcium ions (Ca2+) and reactive oxygen species (ROS) at a single mitochondrion and its surrounding cytosol, thereby enhancing our understanding of their trafficking within the signaling pathways of cellular autophagy. Two independent nanosensors integrated within the channels of the θ-nanopipette spatially isolate a single target mitochondrion from the cytosol and simultaneously measure the release of Ca2+ and ROS with high spatial-temporal resolution. Dynamic tracking reveals the direct trafficking of lysosomal Ca2+ to the mitochondrion rather than to the cytosol, which triggers ROS-induced ROS release within the mitochondria. Furthermore, highly temporal and concurrent observations revealed a second burst of Ca2+ in both the mitochondrion and the cytosol, which is not consistent with the change in ROS. These dynamic data elucidate the potential role of a beneficial feedback loop between the Ca2+ signaling pathway and the subsequent generation of mitochondrial ROS in ML-SA-induced autophagy. More importantly, this innovative platform facilitates detailed profiling of the molecular interactions between trafficking molecules within the mitochondria and the adjacent cytosolic environment, which is hardly realized using the current superresolution optical microscopy.

Keywords:  electrochemical analysis; highly spatial–temporal profiling; molecule trafficking; single living cell; single mitochondrion

DOI:  https://doi.org/10.1073/pnas.2424591122
Curr Cardiol Rev. 2025 Mar 20.

An Updated Review on the Complex Association of Cardiovascular Disease (CVD) and Depression.

Namra Aziz, Tanya Tripathi, Anurag Rawat, Uttam Prasad Panigrahy, Darshan Jc, Mukesh Chandra Sharma, Pranay Wal.

   INTRODUCTION: The presence of both cardiovascular disease (CVD) and depression is common, and their complex connection poses difficulties in therapy and affects patient outcomes. Thus, this study aims to examine the complex correlation between depression and cardiovascular disease (CVD), with a specific focus on potential biomarkers and innovative therapeutic approaches.
METHODS: Publications were considered between 2015-2024 from standard databases like Google Scholar, PUBMED-MEDLINE, and Scopus using standard keywords, "Depression", "cardiovascular disease", "Biomarkers", and "Therapeutic Approaches". Recent studies have discovered several potential biomarkers linked to depression and cardiovascular disease (CVD), including neuroendocrine factors, inflammatory markers, and signs of oxidative stress. Therapeutic approaches for depression and cardiovascular disease have emerged, with a focus on tackling their connections from multiple dimensions.
RESULTS: Emerging research suggests that depression has an impact on both the prognosis and risk of CVD. Conversely, depression can be caused by CVD, which triggers a series of events that lead to higher rates of illness and death.
CONCLUSION: A comprehensive understanding of the fundamental pathophysiological pathways is essential for the identification of biomarkers that can serve as diagnostic tools or therapy targets. Among these interventions, exercise and dietary adjustments have shown promising impacts on cardiovascular health and results, as well as mental health. Ultimately, the selection of diagnostic techniques and treatments hinges on comprehending the complex interplay between depression and CVD. Researchers are developing novel therapeutic techniques to enhance the cardiovascular and mental health outcomes of individuals with both depression and CVD.

Keywords:  Depression; biomarkers; cardiovascular disease; therapeutic approaches.

DOI:  https://doi.org/10.2174/011573403X337113250212093810
3 Biotech. 2025 Apr;15(4): 88

Astaxanthin: a nature's versatile compound utilized for diverse applications and its therapeutic effects.

Anjali Bharti, Vinita Hooda, Utkarsh Jain, Nidhi Chauhan.

  Astaxanthin (ASTX), red-colored xanthophyll, also known as the "king of carotenoids" exhibits a strong antioxidant property that can be naturally found in green algae Haematococcus pluvialis, red yeast Phaffia rhodozyma, and various aquatic species including salmon, krill, trout, and fish eggs. Due to their strong antioxidant qualities, ASTX nanoparticles may be crucial in fighting against phytotoxicity caused by heavy metal ions. Similarly, it may also reduce the uptake of heavy metal, i.e. cadmium, and translocation by improving the morpho-physiological profiles of plants. Furthermore, it can also have the ability to scavenge free radicals, therefore, it can protect plants from reactive oxygen species (ROS). Implementing ASTX nanoparticles on crops can also help to achieve higher food production while minimizing toxic effects. Additionally, it can also possess several therapeutic activities including anti-cancerous, anti-diabetic, antioxidant, anti-aging, anti-inflammation, hepatoprotective, and cardiovascular, etc. that can be beneficial to treat various types of diseases in humans and animals. Recently, it has gained more interest in food, agriculture, aquaculture, neutraceuticals, and pharmaceutical industries due to its wide range of applications including food-coloring agents, food supplements, and strong antioxidant property that helps in skin protection, and boosts immune function. However, ASTX possesses poor water solubility and chemical stability so the implementation of ASTX on human health is facing various issues. Therefore, nanoencapsulation of ASTX is very crucial to improve its chemical stability and solubility, ultimately leading to its bioavailability and bioaccessibility. Recently, ASTX has been commercially available with specific dosages in the market mainly in the form of tablets, gels, powders, creams, syrups, etc. The current review mainly highlights the present state of ASTX nanoparticle applications in various fields explaining its natural and synthetic sources, extraction methods, chemical structure, stability, nanoformulations, nano encapsulation, and various commercial aspects.

Keywords:  Antioxidant activity; Nanoastaxanthin; Nanoformulations; Nano encapsulation; Therapeutic applications

DOI:  https://doi.org/10.1007/s13205-025-04241-5
Curr Mol Pharmacol. 2025 Mar 17.

The Mitochondrial Targeting Drug SkQ1 Attenuates the Progression of Post- Traumatic Osteoarthritis through Suppression of Mitochondrial Oxidative Stress.

Zhen-Ya Zhi, Peng-Cheng Wang.

  Background Post-traumatic osteoarthritis (PTOA) constitutes a distinct subtype of osteoarthritis (OA). Despite extensive research, no effective pharmacological intervention has been established to prevent or halt the progression of PTOA. Current therapeutic approaches are primarily limited to symptomatic management and pain relief. SkQ1, a novel mitochondria-targeted antioxidant, has emerged as a promising therapeutic agent due to its dual capacity to scavenge excessive intracellular reactive oxygen species (ROS) and modulate inflammatory responses. Objective This study aimed to investigate the therapeutic potential of SkQ1 in the early stages of PTOA and elucidate its underlying molecular mechanisms. Methods Chondrocytes were cultured under varying concentrations of SkQ1 to evaluate its cytotoxicity. Additionally, an in vitro oxidative stress model was established to assess the antioxidant effects of SkQ1 across different concentration levels, from which the optimal concentration for PTOA treatment was determined. The rat PTOA model was established through medial meniscal tear (MMT) surgery, followed by intra-articular administration of SkQ1 postoperatively. The gait characteristics of rats in each group were assessed biweekly following surgery. Outcome measures were evaluated at 2 and 6 weeks postoperatively, including pathological evaluation of knee cartilage, ROS levels, markers of oxidative damage, such as malondialdehyde (MDA) and 8-hydroxy-deoxyguanosine (8-OHdG), mitochondrial membrane potential, mitochondrial DNA copy number, and apoptosis-related cytokines. Results In vitro, lower concentrations of SkQ1 (500 nM) exhibited superior antioxidant efficacy while minimizing cytotoxicity. The results indicated that SkQ1 administration significantly enhanced knee joint functionality and mitigated articular cartilage degeneration in both the acute and subacute phases of PTOA by inhibiting oxidative stress pathways. In a rat model of PTOA, SkQ1 not only alleviated gait abnormalities, but also substantially reduced levels of oxidative stress biomarkers, including ROS, MDA, and 8-OHdG. Furthermore, SkQ1 effectively preserved mitochondrial membrane potential and increased mitochondrial DNA copy number. Mechanistically, SkQ1 inhibited the release of cytochrome C (Cyt-C) and apoptosis-inducing factor (AIF) and downregulated key components of the mitochondria-mediated apoptotic pathway, such as Bax, Bak, cleaved caspase-3, and cleaved caspase-9. Conclusion The findings suggested that SkQ1 exerts its therapeutic effects via multiple mechanisms, including the reduction of ROS accumulation, mitigation of oxidative damage, preservation of mitochondrial function, and inhibition of apoptotic pathways. These diverse actions position SkQ1 as a promising disease-modifying agent for PTOA treatment, potentially offering benefits that extend beyond those provided by current symptomfocused therapies.

Keywords:  Apoptosis; Mitochondrial dysfunction.; Oxidative stress; Post-traumatic osteoarthritis; ROS; SkQ1

DOI:  https://doi.org/10.2174/0118761429383749250312082958