Pub Date : 2026-01-13DOI: 10.1016/j.freeradbiomed.2026.01.023
A J García-Yagüe, N Esteras, A T Dinkova-Kostova, A I Rojo, P G Shiels, A Dinnyes, V Tamas, H van Goor, I Lastres-Becker
Parkinson's disease (PD) is a multifactorial neurodegenerative disorder characterized by dopaminergic neuronal loss, α-SYNUCLEIN aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. The transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) orchestrates cellular defense mechanisms by controlling genes involved in antioxidant responses, detoxification, and proteostasis. Impaired NRF2 signaling in PD amplifies oxidative damage, protein misfolding, and inflammatory cascades, whereas NRF2 activation confers broad neuroprotection. This review summarizes evidence from cellular, animal, and human studies delineating NRF2 regulatory roles in redox homeostasis, mitochondrial integrity, and microglial activation. In preclinical models, NRF2 deficiency accelerates neurodegeneration, while pharmacological activation with agents such as dimethyl fumarate, sulforaphane, and synthetic triterpenoids mitigates dopaminergic loss and neuroinflammation. Human studies reveal altered NRF2 pathway components in PD brain and peripheral tissues, and genetic variants in NFE2L2 influence disease susceptibility and progression. Aging, PD's strongest risk factor, reduces NRF2 responsiveness through epigenetic and post-translational changes, promoting oxidative vulnerability and inflammaging. Environmental exposures, including pesticides and pollutants, further modulate NRF2 activity, compounding risk via cumulative "exposome" effects. Understanding NRF2 regulation provides mechanistic insight into PD pathogenesis and positions NRF2 activation as a promising therapeutic strategy for disease modification and healthy brain aging.
{"title":"NRF2 at the crossroads of Parkinson's disease and aging: Mechanistic insights and translational perspectives.","authors":"A J García-Yagüe, N Esteras, A T Dinkova-Kostova, A I Rojo, P G Shiels, A Dinnyes, V Tamas, H van Goor, I Lastres-Becker","doi":"10.1016/j.freeradbiomed.2026.01.023","DOIUrl":"10.1016/j.freeradbiomed.2026.01.023","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a multifactorial neurodegenerative disorder characterized by dopaminergic neuronal loss, α-SYNUCLEIN aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. The transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) orchestrates cellular defense mechanisms by controlling genes involved in antioxidant responses, detoxification, and proteostasis. Impaired NRF2 signaling in PD amplifies oxidative damage, protein misfolding, and inflammatory cascades, whereas NRF2 activation confers broad neuroprotection. This review summarizes evidence from cellular, animal, and human studies delineating NRF2 regulatory roles in redox homeostasis, mitochondrial integrity, and microglial activation. In preclinical models, NRF2 deficiency accelerates neurodegeneration, while pharmacological activation with agents such as dimethyl fumarate, sulforaphane, and synthetic triterpenoids mitigates dopaminergic loss and neuroinflammation. Human studies reveal altered NRF2 pathway components in PD brain and peripheral tissues, and genetic variants in NFE2L2 influence disease susceptibility and progression. Aging, PD's strongest risk factor, reduces NRF2 responsiveness through epigenetic and post-translational changes, promoting oxidative vulnerability and inflammaging. Environmental exposures, including pesticides and pollutants, further modulate NRF2 activity, compounding risk via cumulative \"exposome\" effects. Understanding NRF2 regulation provides mechanistic insight into PD pathogenesis and positions NRF2 activation as a promising therapeutic strategy for disease modification and healthy brain aging.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"760-779"},"PeriodicalIF":8.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145988977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Osteoarthritis (OA), a common degenerative joint disorder, currently lacks effective therapeutic strategies to alleviate its progression. This study aims to investigate the function and underlying mechanisms of dihydrolipoic acid (DHLA) in inhibiting ferroptosis in chondrocytes and alleviating OA progression.
Methods
Mouse primary chondrocytes were exposed to IL-1β to induce ferroptosis and treated with DHLA in vitro, followed by the assessment of ferroptosis-related markers and indicators of chondrocyte anabolism and catabolism. The underlying therapeutic mechanisms of DHLA in OA were further investigated through computer network analysis and experimental validation. The surgery destabilization of the medial meniscus was then conducted to establish the mouse OA model before treatment with DHLA. The therapeutic effect of DHLA in OA mice was evaluated through micro-CT and histological analyses.
Results
DHLA suppressed the IL-1β-induced increases in levels of intracellular reactive oxygen species, Fe2+, lipid peroxidation, and malondialdehyde in chondrocytes, while attenuating the depletion of glutathione, as well as the levels of GPX4 and SLC7A11. Furthermore, the IL-1β-induced reductions in proteoglycans secretion and the levels of Collagen II, Aggrecan, and SOX9 were attenuated by DHLA, while inhibiting the upregulation of MMP13, MMP3, and ADAMTS5. Further studies revealed that the downregulation of FOXO1 expression and the upregulation of TXNIP expression induced by IL-1β were ameliorated by DHLA. The protective effects of DHLA were abolished by AS1842856, a specific FOXO1 inhibitor, whereas this inhibition was reversed by SRI-37330, a specific TXNIP inhibitor. In vivo, DHLA attenuated osteophyte formation and cartilage degeneration induced by DMM surgery in OA model mice. Moreover, the upregulation of MMP13 and TXNIP was suppressed by DHLA, as well as the downregulation of Collagen II, GPX4, and FOXO1 in articular cartilage.
Conclusion
DHLA inhibits chondrocytes ferroptosis to alleviate OA progression through the FOXO1/TXNIP signaling pathway, offering a potential treatment strategy for OA.
{"title":"Dihydrolipoic acid suppresses ferroptosis in chondrocytes to ameliorate the progression of osteoarthritis by modulating the FOXO1/TXNIP signaling pathway","authors":"Yitao Chen , Jiawei Fang , Zhiguo Zhou , Haiwei Ma, Shijie Liu, Hehuan Lai, Yahong Lu, Yu Bai, XingYu Hu, Zhenzhong Chen, Feijun Liu, Dengwei He","doi":"10.1016/j.freeradbiomed.2026.01.021","DOIUrl":"10.1016/j.freeradbiomed.2026.01.021","url":null,"abstract":"<div><h3>Background</h3><div>Osteoarthritis (OA), a common degenerative joint disorder, currently lacks effective therapeutic strategies to alleviate its progression. This study aims to investigate the function and underlying mechanisms of dihydrolipoic acid (DHLA) in inhibiting ferroptosis in chondrocytes and alleviating OA progression.</div></div><div><h3>Methods</h3><div>Mouse primary chondrocytes were exposed to IL-1β to induce ferroptosis and treated with DHLA in vitro, followed by the assessment of ferroptosis-related markers and indicators of chondrocyte anabolism and catabolism. The underlying therapeutic mechanisms of DHLA in OA were further investigated through computer network analysis and experimental validation. The surgery destabilization of the medial meniscus was then conducted to establish the mouse OA model before treatment with DHLA. The therapeutic effect of DHLA in OA mice was evaluated through micro-CT and histological analyses.</div></div><div><h3>Results</h3><div>DHLA suppressed the IL-1β-induced increases in levels of intracellular reactive oxygen species, Fe<sup>2+</sup>, lipid peroxidation, and malondialdehyde in chondrocytes, while attenuating the depletion of glutathione, as well as the levels of GPX4 and SLC7A11. Furthermore, the IL-1β-induced reductions in proteoglycans secretion and the levels of Collagen II, Aggrecan, and SOX9 were attenuated by DHLA, while inhibiting the upregulation of MMP13, MMP3, and ADAMTS5. Further studies revealed that the downregulation of FOXO1 expression and the upregulation of TXNIP expression induced by IL-1β were ameliorated by DHLA. The protective effects of DHLA were abolished by AS1842856, a specific FOXO1 inhibitor, whereas this inhibition was reversed by SRI-37330, a specific TXNIP inhibitor. In vivo, DHLA attenuated osteophyte formation and cartilage degeneration induced by DMM surgery in OA model mice. Moreover, the upregulation of MMP13 and TXNIP was suppressed by DHLA, as well as the downregulation of Collagen II, GPX4, and FOXO1 in articular cartilage.</div></div><div><h3>Conclusion</h3><div>DHLA inhibits chondrocytes ferroptosis to alleviate OA progression through the FOXO1/TXNIP signaling pathway, offering a potential treatment strategy for OA.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 169-180"},"PeriodicalIF":8.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145988982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-12DOI: 10.1016/j.freeradbiomed.2026.01.016
Zhuolin Du , Xingwu Liu , Yanhan Yang , Xudong Min , Jirui Wei , Yang She , Abudushalamu Abulaiti , Xiayu Jin , Zequn Su , Shizhong Zhang , Jian Liu , Karrie M. Kiang , Gilberto Ka-Kit Leung , Xiaozheng He , Zhiyuan Zhu
Mitochondrial integrity is essential for tumor cell proliferation and survival. Our previous study has demonstrated the oncogenic role of the metabolic enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) in glioblastoma (GBM). Given that the non-metabolic function of certain enzymes has been reported, we aim to interrogate whether MTHFD2 has potential roles in mitochondrial integrity and dynamics, especially beyond catabolism. By using multi-faceted approaches including single-cell RNA sequencing, mt-Keima mitophagy flux assays, RNA immunoprecipitation sequencing and luciferase reporter assays, we elucidated a novel, non-canonical function of MTHFD2 in stabilizing mRNA in GBM. We found that MTHFD2 was upregulated in GBM and was enriched in specific tumor subtypes cells such as ependymal-like and OPC-like cells. Knockdown of MTHFD2 profoundly promoted mitochondrial fission that triggered excessive mitophagy and cellular apoptosis. Mechanistically, MTHFD2 directly bound to the 3′-untranslated region (3′-UTR) of TOP2A mRNA and enhanced its stability, implying the RNA binding function of this catabolic enzyme. Overexpression of TOP2A attenuated mitophagy and cellular apoptosis induced by MTHFD2 depletion, indicating a vital role of MTHFD2-TOP2A axis in modulating mitochondrial integrity. Importantly, targeting MTHFD2 impeded GBM growth in orthotopic mouse models, which could be a promising therapeutic strategy. In conclusion, we proposed a non-canonical function of MTHFD2, which bound to and stabilized the mRNA of TOP2A. Targeting MTHFD2 triggered excessive mitophagy and cell apoptosis in GBM via destabilizing TOP2A mRNA.
{"title":"The non-metabolic role of MTHFD2 in regulating mitochondrial fission-dependent mitophagy via stabilizing TOP2A mRNA in glioblastoma","authors":"Zhuolin Du , Xingwu Liu , Yanhan Yang , Xudong Min , Jirui Wei , Yang She , Abudushalamu Abulaiti , Xiayu Jin , Zequn Su , Shizhong Zhang , Jian Liu , Karrie M. Kiang , Gilberto Ka-Kit Leung , Xiaozheng He , Zhiyuan Zhu","doi":"10.1016/j.freeradbiomed.2026.01.016","DOIUrl":"10.1016/j.freeradbiomed.2026.01.016","url":null,"abstract":"<div><div>Mitochondrial integrity is essential for tumor cell proliferation and survival. Our previous study has demonstrated the oncogenic role of the metabolic enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) in glioblastoma (GBM). Given that the non-metabolic function of certain enzymes has been reported, we aim to interrogate whether MTHFD2 has potential roles in mitochondrial integrity and dynamics, especially beyond catabolism. By using multi-faceted approaches including single-cell RNA sequencing, mt-Keima mitophagy flux assays, RNA immunoprecipitation sequencing and luciferase reporter assays, we elucidated a novel, non-canonical function of MTHFD2 in stabilizing mRNA in GBM. We found that MTHFD2 was upregulated in GBM and was enriched in specific tumor subtypes cells such as ependymal-like and OPC-like cells. Knockdown of MTHFD2 profoundly promoted mitochondrial fission that triggered excessive mitophagy and cellular apoptosis. Mechanistically, MTHFD2 directly bound to the 3′-untranslated region (3′-UTR) of TOP2A mRNA and enhanced its stability, implying the RNA binding function of this catabolic enzyme. Overexpression of TOP2A attenuated mitophagy and cellular apoptosis induced by MTHFD2 depletion, indicating a vital role of MTHFD2-TOP2A axis in modulating mitochondrial integrity. Importantly, targeting MTHFD2 impeded GBM growth in orthotopic mouse models, which could be a promising therapeutic strategy. In conclusion, we proposed a non-canonical function of MTHFD2, which bound to and stabilized the mRNA of TOP2A. Targeting MTHFD2 triggered excessive mitophagy and cell apoptosis in GBM via destabilizing TOP2A mRNA.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 93-106"},"PeriodicalIF":8.2,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145957675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cetuximab resistance in head and neck squamous cell carcinoma (HNSCC) is increasingly recognized as an adaptive state driven by metabolic and redox reprogramming that enables tumor cells to tolerate sustained oxidative and immune stress. Although lipid metabolism and PPARγ signaling have been implicated in therapeutic resistance, their functional contribution to drug-tolerant persister (DTP) cells and the role of peroxisomal fatty acid oxidation (FAO) remain poorly defined. In this study, we demonstrate that a redox-driven FABP1/PPARγ axis sustains peroxisome-centered FAO, GPX4-dependent antioxidant defense, and immune suppression in cetuximab-tolerant HNSCC. FABP1 expression was markedly elevated in cetuximab-tolerant DTP cell models and resistant patient tumors. Genetic silencing or pharmacological inhibition of FABP1 using a selective small-molecule inhibitor impaired tumorsphere formation, increased intracellular reactive oxygen species accumulation, and induced apoptotic cell death, accompanied by coordinated suppression of FAO-associated genes, including CPT1, ACSL family members, and acyl-CoA oxidase 1. In an orthotopic SCC9-DTP xenograft model established in NOD-SCID mice, FABP1 inhibition significantly attenuated tumor growth, disrupted metabolic–redox adaptation, and reduced tumor-associated macrophage polarization toward an immunosuppressive phenotype. Our findings identify the FABP1/PPARγ axis as a central regulator of peroxisome-centered FAO and redox buffering in cetuximab-tolerant DTP cells. Targeting FABP1 collapses this adaptive metabolic–redox program, restores vulnerability to oxidative stress, and alleviates immune suppression, highlighting peroxisomal lipid metabolism as a therapeutically actionable vulnerability in refractory HNSCC.
{"title":"Redox-driven FABP1/PPARγ signaling fuels peroxisomal fatty acid oxidation and confers cetuximab resistance in drug-tolerant head and neck cancer cells","authors":"Hang Huong Ling , Chin-Sheng Huang , Ming-Shou Hsieh , Vijesh Kumar Yadav , Iat-Hang Fong , Kuang-Tai Kuo , Chi-Tai Yeh , Jo-Ting Tsai","doi":"10.1016/j.freeradbiomed.2026.01.020","DOIUrl":"10.1016/j.freeradbiomed.2026.01.020","url":null,"abstract":"<div><div>Cetuximab resistance in head and neck squamous cell carcinoma (HNSCC) is increasingly recognized as an adaptive state driven by metabolic and redox reprogramming that enables tumor cells to tolerate sustained oxidative and immune stress. Although lipid metabolism and PPARγ signaling have been implicated in therapeutic resistance, their functional contribution to drug-tolerant persister (DTP) cells and the role of peroxisomal fatty acid oxidation (FAO) remain poorly defined. In this study, we demonstrate that a redox-driven FABP1/PPARγ axis sustains peroxisome-centered FAO, GPX4-dependent antioxidant defense, and immune suppression in cetuximab-tolerant HNSCC. FABP1 expression was markedly elevated in cetuximab-tolerant DTP cell models and resistant patient tumors. Genetic silencing or pharmacological inhibition of FABP1 using a selective small-molecule inhibitor impaired tumorsphere formation, increased intracellular reactive oxygen species accumulation, and induced apoptotic cell death, accompanied by coordinated suppression of FAO-associated genes, including CPT1, ACSL family members, and acyl-CoA oxidase 1. In an orthotopic SCC9-DTP xenograft model established in NOD-SCID mice, FABP1 inhibition significantly attenuated tumor growth, disrupted metabolic–redox adaptation, and reduced tumor-associated macrophage polarization toward an immunosuppressive phenotype. Our findings identify the FABP1/PPARγ axis as a central regulator of peroxisome-centered FAO and redox buffering in cetuximab-tolerant DTP cells. Targeting FABP1 collapses this adaptive metabolic–redox program, restores vulnerability to oxidative stress, and alleviates immune suppression, highlighting peroxisomal lipid metabolism as a therapeutically actionable vulnerability in refractory HNSCC.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 209-222"},"PeriodicalIF":8.2,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-12DOI: 10.1016/j.freeradbiomed.2026.01.019
Zhe Gong , Ziyi Chen , Shuixian Sang , Lingfei Yang , Hongzhuo Qin , Qingsheng Li , Yanjie Jia
Background
Vascular cognitive impairment (VCI) is strongly associated with mitochondrial dysfunction, yet the underlying molecular mechanisms connecting mitochondrial impairment to neuroinflammation remain elusive. While mitochondrial epigenetic modifications are emerging as key regulators of cellular metabolism, the role of mitochondrial DNA (mtDNA) N6-methyladenine (6 mA) modification and its writer enzyme METTL4 in VCI pathogenesis has not been established.
Methods
Using complementary in vitro (oxygen-glucose deprivation, OGD) and in vivo (chronic cerebral hypoperfusion, CCH) models of VCI, we systematically investigated METTL4-mediated mtDNA epigenetic regulation. Approaches included RNA sequencing (RNA-seq), mitochondrial functional assays, reactive oxygen species (ROS) measurement, and comprehensive analysis of cGAS-STING-mediated neuroinflammatory responses.
Results
We identified mitochondrial-specific enrichment of METTL4 in hippocampal neurons, with significantly elevated mtDNA 6 mA levels following CCH. Mechanistically, OGD-induced METTL4 preferentially methylated the light-strand promoter region of mtDNA, leading to (Dichgans and Leys, 2017) [1]: impaired electron transport chain (ETC) activity (Kim et al., 2020) [2], excessive ROS production, and (Johnson, 2023) [3] oxidized mtDNA leakage. These mitochondrial abnormalities robustly activated the cGAS-STING neuroinflammatory pathway. Genetic inhibition of METTL4 normalized 6 mA levels, restored mitochondrial gene expression profiles, and significantly improved cognitive function in VCI models.
Conclusion
Our study delineates a complete METTL4-mtDNA 6 mA-mitochondrial dysfunction-neuroinflammation axis in VCI pathogenesis. These findings not only provide novel insights into the epigenetic control of neuroinflammation but also position METTL4 as a promising therapeutic target for mitigating cerebrovascular-related cognitive decline.
血管性认知障碍（VCI）与线粒体功能障碍密切相关，但线粒体损伤与神经炎症之间的潜在分子机制尚不清楚。虽然线粒体表观遗传修饰已成为细胞代谢的关键调节因子，但线粒体DNA (mtDNA) n6 -甲基腺嘌呤（6ma）修饰及其书写酶METTL4在VCI发病机制中的作用尚未确定。方法采用体外（氧-葡萄糖剥夺，OGD）和体内（慢性脑灌注不足，CCH）模型，系统研究mettl4介导的mtDNA表观遗传调控。方法包括RNA测序（RNA-seq）、线粒体功能测定、活性氧（ROS）测定以及cgas - sting介导的神经炎症反应的综合分析。结果我们在海马神经元中发现线粒体特异性的METTL4富集，CCH后mtDNA 6 mA水平显著升高。在机制上，ogd诱导的METTL4优先甲基化mtDNA的光链启动子区域，导致（Dichgans and Leys, 2017）[1]；电子传递链（ETC）活性受损（Kim et al., 2020）[1]；过量的ROS产生，以及（Johnson, 2023）[3]氧化mtDNA泄漏。这些线粒体异常强有力地激活了cGAS-STING神经炎症通路。基因抑制METTL4使6ma水平正常化，恢复线粒体基因表达谱，并显著改善VCI模型的认知功能。结论本研究描绘了VCI发病过程中完整的METTL4-mtDNA - 6ma -线粒体功能障碍-神经炎症轴。这些发现不仅为神经炎症的表观遗传控制提供了新的见解，而且将METTL4定位为缓解脑血管相关认知能力下降的有希望的治疗靶点。
{"title":"Mitochondrial DNA 6 mA methylation by METTL4 drives neuroinflammation via cGAS-STING activation in vascular cognitive impairment","authors":"Zhe Gong , Ziyi Chen , Shuixian Sang , Lingfei Yang , Hongzhuo Qin , Qingsheng Li , Yanjie Jia","doi":"10.1016/j.freeradbiomed.2026.01.019","DOIUrl":"10.1016/j.freeradbiomed.2026.01.019","url":null,"abstract":"<div><h3>Background</h3><div>Vascular cognitive impairment (VCI) is strongly associated with mitochondrial dysfunction, yet the underlying molecular mechanisms connecting mitochondrial impairment to neuroinflammation remain elusive. While mitochondrial epigenetic modifications are emerging as key regulators of cellular metabolism, the role of mitochondrial DNA (mtDNA) N<sup>6</sup>-methyladenine (6 mA) modification and its writer enzyme METTL4 in VCI pathogenesis has not been established.</div></div><div><h3>Methods</h3><div>Using complementary in <em>vitro</em> (oxygen-glucose deprivation, OGD) and in <em>vivo</em> (chronic cerebral hypoperfusion, CCH) models of VCI, we systematically investigated METTL4-mediated mtDNA epigenetic regulation. Approaches included RNA sequencing (RNA-seq), mitochondrial functional assays, reactive oxygen species (ROS) measurement, and comprehensive analysis of cGAS-STING-mediated neuroinflammatory responses.</div></div><div><h3>Results</h3><div>We identified mitochondrial-specific enrichment of METTL4 in hippocampal neurons, with significantly elevated mtDNA 6 mA levels following CCH. Mechanistically, OGD-induced METTL4 preferentially methylated the light-strand promoter region of mtDNA, leading to (Dichgans and Leys, 2017) [1]: impaired electron transport chain (ETC) activity (Kim et al., 2020) [2], excessive ROS production, and (Johnson, 2023) [3] oxidized mtDNA leakage. These mitochondrial abnormalities robustly activated the cGAS-STING neuroinflammatory pathway. Genetic inhibition of METTL4 normalized 6 mA levels, restored mitochondrial gene expression profiles, and significantly improved cognitive function in VCI models.</div></div><div><h3>Conclusion</h3><div>Our study delineates a complete METTL4-mtDNA 6 mA-mitochondrial dysfunction-neuroinflammation axis in VCI pathogenesis. These findings not only provide novel insights into the epigenetic control of neuroinflammation but also position METTL4 as a promising therapeutic target for mitigating cerebrovascular-related cognitive decline.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 1-16"},"PeriodicalIF":8.2,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145957654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-11DOI: 10.1016/j.freeradbiomed.2026.01.018
Chao Li , MingZhi Ou , GuiXian Zheng , Gang Jiang , Xiao Hu , YongLiang Jiang
Skeletal muscle atrophy, a debilitating complication of COPD, is closely linked to cigarette smoke (CS) exposure. The epigenetic regulator HDAC2 has been implicated, but the upstream regulatory mechanisms and precise downstream pathways are unclear. Using a CS-induced mouse atrophy model and C2C12 myotubes treated with cigarette smoke extract (CSE), we systematically investigated the role of USP47/HDAC2/CYP1A1/ROS axis through gain/loss-of-function studies, RNA-seq, ChIP-qPCR, co-immunoprecipitation, and ubiquitination assays. HDAC2 was downregulated in atrophic muscle, and its overexpression mitigated CS-induced atrophy, improved grip strength, and enhanced muscle regeneration. HDAC2 acted as a transcriptional repressor of CYP1A1 by deacetylating H3K9 and H3K27 at the promoter, thus curtailing ROS-driven excessive autophagy. We further discovered that the deubiquitinase USP47 is the key upstream regulator of HDAC2. USP47 directly interacted with HDAC2, promoted its deubiquitination, and enhanced its protein stability. Consequently, USP47 overexpression phenocopied the benefits of HDAC2 overexpression, which were effectively nullified by restoring CYP1A1 expression. In conclusion, we delineate a previously unrecognized signaling axis wherein USP47 stabilizes HDAC2 to inhibit the CYP1A1/ROS/autophagy cascade, ultimately protecting against CS-induced skeletal muscle atrophy. Targeting the USP47-HDAC2 interface presents a novel therapeutic strategy for combating muscle wasting in COPD.
{"title":"USP47 stabilizes HDAC2 to ameliorate cigarette smoke-induced skeletal muscle atrophy by suppressing CYP1A1/ROS-mediated autophagy","authors":"Chao Li , MingZhi Ou , GuiXian Zheng , Gang Jiang , Xiao Hu , YongLiang Jiang","doi":"10.1016/j.freeradbiomed.2026.01.018","DOIUrl":"10.1016/j.freeradbiomed.2026.01.018","url":null,"abstract":"<div><div>Skeletal muscle atrophy, a debilitating complication of COPD, is closely linked to cigarette smoke (CS) exposure. The epigenetic regulator HDAC2 has been implicated, but the upstream regulatory mechanisms and precise downstream pathways are unclear. Using a CS-induced mouse atrophy model and C2C12 myotubes treated with cigarette smoke extract (CSE), we systematically investigated the role of USP47/HDAC2/CYP1A1/ROS axis through gain/loss-of-function studies, RNA-seq, ChIP-qPCR, co-immunoprecipitation, and ubiquitination assays. HDAC2 was downregulated in atrophic muscle, and its overexpression mitigated CS-induced atrophy, improved grip strength, and enhanced muscle regeneration. HDAC2 acted as a transcriptional repressor of CYP1A1 by deacetylating H3K9 and H3K27 at the promoter, thus curtailing ROS-driven excessive autophagy. We further discovered that the deubiquitinase USP47 is the key upstream regulator of HDAC2. USP47 directly interacted with HDAC2, promoted its deubiquitination, and enhanced its protein stability. Consequently, USP47 overexpression phenocopied the benefits of HDAC2 overexpression, which were effectively nullified by restoring CYP1A1 expression. In conclusion, we delineate a previously unrecognized signaling axis wherein USP47 stabilizes HDAC2 to inhibit the CYP1A1/ROS/autophagy cascade, ultimately protecting against CS-induced skeletal muscle atrophy. Targeting the USP47-HDAC2 interface presents a novel therapeutic strategy for combating muscle wasting in COPD.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 107-125"},"PeriodicalIF":8.2,"publicationDate":"2026-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145965650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-09DOI: 10.1016/j.freeradbiomed.2026.01.015
Yixiao Xu , Yishun Gong , Jiafa Zhong , Jiucun Wang , Binghong Gao
Objective
Active heat acclimation is widely used by athletes or workers exposed to heat, yet its impact on skeletal muscle mitochondrial function and the underlying molecular regulators remain incompletely understood. This study aimed to investigate how active heat acclimation improves skeletal muscle mitochondrial function, with a specific focus on transient receptor potential vanilloid 1 (TRPV1) as an important mediator.
Methods
A 4-week intervention was conducted in trained runners (exercise in heat vs. thermoneutral conditions) and in mice exposed to heat, exercise, TRPV1 activation (nonivamide), or TRPV1 inhibition (AMG9810). Aerobic performance, substrate utilization, mitochondrial respiration, H2O2 emission, mitochondrial ultrastructure, and molecular markers of biogenesis and mitophagy were assessed.
Results
In humans, active heat acclimation improved ventilatory thresholds, enhanced lactate clearance, and reduced carbohydrate oxidation during submaximal exercise. In mice, active heat acclimation increased mitochondrial biogenesis (PGC-1α, p-p38 MAPK, TFAM), enhanced mitophagy (Pink1, Parkin), improved OXPHOS and ETS capacities, and elevated TRPV1 expression. Pharmacological TRPV1 activation augmented mitochondrial remodeling and improved exercise performance. Conversely, TRPV1 inhibition blunted heat-induced mitochondrial biogenesis, mitophagy activation, and structural remodeling.
Conclusion
TRPV1 is an important mediator of mitochondrial adaptations to active heat acclimation, promoting mitochondrial turnover and enhancing respiratory capacity, thereby supporting the improvement of aerobic capacity.
{"title":"TRPV1 activation by active heat acclimation drives skeletal muscle mitochondrial turnover","authors":"Yixiao Xu , Yishun Gong , Jiafa Zhong , Jiucun Wang , Binghong Gao","doi":"10.1016/j.freeradbiomed.2026.01.015","DOIUrl":"10.1016/j.freeradbiomed.2026.01.015","url":null,"abstract":"<div><h3>Objective</h3><div>Active heat acclimation is widely used by athletes or workers exposed to heat, yet its impact on skeletal muscle mitochondrial function and the underlying molecular regulators remain incompletely understood. This study aimed to investigate how active heat acclimation improves skeletal muscle mitochondrial function, with a specific focus on transient receptor potential vanilloid 1 (TRPV1) as an important mediator.</div></div><div><h3>Methods</h3><div>A 4-week intervention was conducted in trained runners (exercise in heat vs. thermoneutral conditions) and in mice exposed to heat, exercise, TRPV1 activation (nonivamide), or TRPV1 inhibition (AMG9810). Aerobic performance, substrate utilization, mitochondrial respiration, H<sub>2</sub>O<sub>2</sub> emission, mitochondrial ultrastructure, and molecular markers of biogenesis and mitophagy were assessed.</div></div><div><h3>Results</h3><div>In humans, active heat acclimation improved ventilatory thresholds, enhanced lactate clearance, and reduced carbohydrate oxidation during submaximal exercise. In mice, active heat acclimation increased mitochondrial biogenesis (PGC-1α, p-p38 MAPK, TFAM), enhanced mitophagy (Pink1, Parkin), improved OXPHOS and ETS capacities, and elevated TRPV1 expression. Pharmacological TRPV1 activation augmented mitochondrial remodeling and improved exercise performance. Conversely, TRPV1 inhibition blunted heat-induced mitochondrial biogenesis, mitophagy activation, and structural remodeling.</div></div><div><h3>Conclusion</h3><div>TRPV1 is an important mediator of mitochondrial adaptations to active heat acclimation, promoting mitochondrial turnover and enhancing respiratory capacity, thereby supporting the improvement of aerobic capacity.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 368-380"},"PeriodicalIF":8.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-09DOI: 10.1016/j.freeradbiomed.2025.12.060
Youyi Wu , Dan Chen , Xiaohu Wang , Mengyao Song , Jingyi Wu , Shunlong Wu , Kui Liao
Breast cancer is one of the most common malignancies and a leading cause of mortality among women worldwide. Triple-negative breast cancer (TNBC) accounts for 15–20 % of all breast cancer cases and is characterized by poor prognosis, high invasiveness, and a propensity for metastasis. Radiotherapy is a crucial component of multimodal therapy for TNBC, serving primarily as an adjuvant modality following surgery or for local control in locally advanced disease. However, tumor tissues gradually adapt to radiation exposure, leading to the development of radioresistance—a phenomenon where cancer cells survive and proliferate despite radiotherapy, significantly compromising treatment efficacy and patient outcomes. In recent years, numerous studies have reported that the herbal compound dihydroartemisinin (DHA) may serve as a radiosensitizer to enhance tumor sensitivity to radiation while reducing radiotoxicity in surrounding normal tissues. Nevertheless, the underlying mechanisms remain insufficient to meet clinical translation demands. Thus, identifying novel targets and alternative sensitization mechanisms is urgently needed. Here, we report that DHA overcomes acquired radioresistance by orchestrating a novel autophagy-dependent ferroptosis pathway. We demonstrate that DHA directly binds to and promotes the ubiquitination-mediated degradation of GPX4, a key guardian against ferroptosis. This degradation leads to intracellular Fe2+ accumulation and lethal lipid peroxidation. Crucially, we establish that autophagy acts as an essential upstream mechanism enabling GPX4 degradation, thereby bridging DHA-induced stress to ferroptotic execution. Both Atg5 knockdown and pharmacological inhibition of autophagy prevented DHA-induced GPX4 loss and the consequent radiosensitization. Collectively, our findings reveal a previously unrecognized mechanism in which DHA overcomes TNBC radioresistance by co-opting the autophagy pathway to degrade GPX4 and unleash ferroptosis, presenting a promising therapeutic paradigm targeting the autophagy-ferroptosis axis for refractory TNBC.
{"title":"Dihydroartemisinin targets GPX4 to induce autophagy-dependent ferroptosis and reduce radioresistance in triple-negative breast cancer","authors":"Youyi Wu , Dan Chen , Xiaohu Wang , Mengyao Song , Jingyi Wu , Shunlong Wu , Kui Liao","doi":"10.1016/j.freeradbiomed.2025.12.060","DOIUrl":"10.1016/j.freeradbiomed.2025.12.060","url":null,"abstract":"<div><div>Breast cancer is one of the most common malignancies and a leading cause of mortality among women worldwide. Triple-negative breast cancer (TNBC) accounts for 15–20 % of all breast cancer cases and is characterized by poor prognosis, high invasiveness, and a propensity for metastasis. Radiotherapy is a crucial component of multimodal therapy for TNBC, serving primarily as an adjuvant modality following surgery or for local control in locally advanced disease. However, tumor tissues gradually adapt to radiation exposure, leading to the development of radioresistance—a phenomenon where cancer cells survive and proliferate despite radiotherapy, significantly compromising treatment efficacy and patient outcomes. In recent years, numerous studies have reported that the herbal compound dihydroartemisinin (DHA) may serve as a radiosensitizer to enhance tumor sensitivity to radiation while reducing radiotoxicity in surrounding normal tissues. Nevertheless, the underlying mechanisms remain insufficient to meet clinical translation demands. Thus, identifying novel targets and alternative sensitization mechanisms is urgently needed. Here, we report that DHA overcomes acquired radioresistance by orchestrating a novel autophagy-dependent ferroptosis pathway. We demonstrate that DHA directly binds to and promotes the ubiquitination-mediated degradation of GPX4, a key guardian against ferroptosis. This degradation leads to intracellular Fe<sup>2+</sup> accumulation and lethal lipid peroxidation. Crucially, we establish that autophagy acts as an essential upstream mechanism enabling GPX4 degradation, thereby bridging DHA-induced stress to ferroptotic execution. Both Atg5 knockdown and pharmacological inhibition of autophagy prevented DHA-induced GPX4 loss and the consequent radiosensitization. Collectively, our findings reveal a previously unrecognized mechanism in which DHA overcomes TNBC radioresistance by co-opting the autophagy pathway to degrade GPX4 and unleash ferroptosis, presenting a promising therapeutic paradigm targeting the autophagy-ferroptosis axis for refractory TNBC.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 35-50"},"PeriodicalIF":8.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-09DOI: 10.1016/j.freeradbiomed.2026.01.010
Jonathan Hermenejildo , María Pelechá-Salvador , Meylin Fernández-Reyes , Laura Perea-Galera , Jordi Mota-Plaza , Javier Silvestre-Rangil , Celia Bañuls , Carlos Morillas , Francisco Javier Silvestre , Víctor M. Víctor , Sandra López-Domènech , Milagros Rocha
Introduction
Chronic periodontitis (CP) is an inflammatory disease associated with local and systemic oxidative stress and leads to mitochondrial homeostasis disruption. Although non-surgical periodontal therapy (NSPT) has been proved to reduce the bacterial load and inflammation, the mechanisms underlying its effects on mitochondrial function and systemic redox balance remain poorly understood.
Methods
Eighty patients with CP underwent NSPT. Clinical, anthropometric, and biochemical parameters were evaluated at baseline and 12 weeks after therapy. Mitochondrial redox status, membrane potential, markers of mitochondrial biogenic signalling (PGC-1α), electron transport chain (ETC) complexes, and bioenergetic function were assessed in peripheral blood mononuclear cells (PBMCs). Correlation and multivariable analyses were performed to explore relationships between periodontal improvement and mitochondrial parameters.
Results
After NSPT, patients presented significant reductions in mitochondrial ROS and increased GPX1 expression. PBMCs also showed elevated PGC-1α and ETC I–IV protein levels, together with enhanced mitochondrial membrane potential, mass, and spare respiratory capacity. Baseline mitochondrial parameters were associated with the percentage of reduction of periodontal clinical parameters following NSPT.
Conclusions
NSPT not only ameliorates local periodontal inflammation but also modulates mitochondrial-related homeostasis and bioenergetic efficiency in circulating immune cells. The present findings support mitochondrial remodelling as a systemic mechanism underlying the benefits of periodontal therapy and a promising target for the treatment of inflammation-related comorbidities.
{"title":"Non-surgical periodontal treatment improves mitochondrial bioenergetics in circulating immune cells of patients with chronic periodontitis","authors":"Jonathan Hermenejildo , María Pelechá-Salvador , Meylin Fernández-Reyes , Laura Perea-Galera , Jordi Mota-Plaza , Javier Silvestre-Rangil , Celia Bañuls , Carlos Morillas , Francisco Javier Silvestre , Víctor M. Víctor , Sandra López-Domènech , Milagros Rocha","doi":"10.1016/j.freeradbiomed.2026.01.010","DOIUrl":"10.1016/j.freeradbiomed.2026.01.010","url":null,"abstract":"<div><h3>Introduction</h3><div>Chronic periodontitis (CP) is an inflammatory disease associated with local and systemic oxidative stress and leads to mitochondrial homeostasis disruption. Although non-surgical periodontal therapy (NSPT) has been proved to reduce the bacterial load and inflammation, the mechanisms underlying its effects on mitochondrial function and systemic redox balance remain poorly understood.</div></div><div><h3>Methods</h3><div>Eighty patients with CP underwent NSPT. Clinical, anthropometric, and biochemical parameters were evaluated at baseline and 12 weeks after therapy. Mitochondrial redox status, membrane potential, markers of mitochondrial biogenic signalling (PGC-1α), electron transport chain (ETC) complexes, and bioenergetic function were assessed in peripheral blood mononuclear cells (PBMCs). Correlation and multivariable analyses were performed to explore relationships between periodontal improvement and mitochondrial parameters.</div></div><div><h3>Results</h3><div>After NSPT, patients presented significant reductions in mitochondrial ROS and increased GPX1 expression. PBMCs also showed elevated PGC-1α and ETC I–IV protein levels, together with enhanced mitochondrial membrane potential, mass, and spare respiratory capacity. Baseline mitochondrial parameters were associated with the percentage of reduction of periodontal clinical parameters following NSPT.</div></div><div><h3>Conclusions</h3><div>NSPT not only ameliorates local periodontal inflammation but also modulates mitochondrial-related homeostasis and bioenergetic efficiency in circulating immune cells. The present findings support mitochondrial remodelling as a systemic mechanism underlying the benefits of periodontal therapy and a promising target for the treatment of inflammation-related comorbidities.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 159-168"},"PeriodicalIF":8.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-09DOI: 10.1016/j.freeradbiomed.2026.01.002
Anders Gudiksen, Camilla Collin Hansen, Thibaux van der Stede, Amalie Hertz Daugaard, Josefine H Schmidt, Stine Ringholm, Manal Merimi, Fatima Raad Al-Obaidi, Amanda Takamiya Kristoffersen, Egija Zole, Birgitte Regenberg, Rasmus Kjøbsted, Jørgen Wojtaszewski, Ylva Hellsten, Henriette Pilegaard
Mitochondrial-derived peptides are a small class of regulatory peptides encoded by short open reading frames in mitochondrial DNA. One such peptide, mitochondrial open reading frame of the 12S rRNA-c (MOTS-c), has been shown to exert numerous beneficial effects on whole-cell and systemic metabolic parameters when administered exogenously. However, potential MOTS-c-mediated effects on mitochondrial bioenergetics have been largely overlooked. Therefore, the primary aim of the present study was to elucidate whether and, if so, how MOTS-c regulates skeletal muscle (SkM) mitochondrial function. We demonstrate, using two distinct transgenic mouse strains, that administration of MOTS-c augments muscle mitochondrial bioenergetic performance through reliance on both the transcriptional coactivator, Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), and cellular energy-sensing kinase, 5' adenosine monophosphate-activated protein kinase (AMPK). These effects seem to be exerted without apparent impact on mitochondrial respiratory protein content, alluding to intrinsic mitochondrial changes rather than changes in volume. Furthermore, MOTS-c treatment lowers mitochondrial reactive oxygen species (ROS) emission and ROS-related protein damage indicating substantial alleviation of cellular oxidative stress. RNA-sequence data reveal the effects of MOTS-c treatment to potentially be exerted subtly across a number of mitochondrial parameters such as redox handling, mitochondrial integrity and OXPHOS efficiency, jointly indicating a mechanistic basis for the observed functional improvements in mitochondrial bioenergetics. Despite increased interstitial MOTS-c levels no change was observed in the arterio-venous difference during one-legged knee extensor exercise in humans. This suggests that SkM may not be the source of circulating MOTS-c in response to exercise.
{"title":"MOTS-c improves intrinsic muscle mitochondrial bioenergetic health and efficiency in a PGC-1α/AMPK-dependent manner.","authors":"Anders Gudiksen, Camilla Collin Hansen, Thibaux van der Stede, Amalie Hertz Daugaard, Josefine H Schmidt, Stine Ringholm, Manal Merimi, Fatima Raad Al-Obaidi, Amanda Takamiya Kristoffersen, Egija Zole, Birgitte Regenberg, Rasmus Kjøbsted, Jørgen Wojtaszewski, Ylva Hellsten, Henriette Pilegaard","doi":"10.1016/j.freeradbiomed.2026.01.002","DOIUrl":"10.1016/j.freeradbiomed.2026.01.002","url":null,"abstract":"<p><p>Mitochondrial-derived peptides are a small class of regulatory peptides encoded by short open reading frames in mitochondrial DNA. One such peptide, mitochondrial open reading frame of the 12S rRNA-c (MOTS-c), has been shown to exert numerous beneficial effects on whole-cell and systemic metabolic parameters when administered exogenously. However, potential MOTS-c-mediated effects on mitochondrial bioenergetics have been largely overlooked. Therefore, the primary aim of the present study was to elucidate whether and, if so, how MOTS-c regulates skeletal muscle (SkM) mitochondrial function. We demonstrate, using two distinct transgenic mouse strains, that administration of MOTS-c augments muscle mitochondrial bioenergetic performance through reliance on both the transcriptional coactivator, Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), and cellular energy-sensing kinase, 5' adenosine monophosphate-activated protein kinase (AMPK). These effects seem to be exerted without apparent impact on mitochondrial respiratory protein content, alluding to intrinsic mitochondrial changes rather than changes in volume. Furthermore, MOTS-c treatment lowers mitochondrial reactive oxygen species (ROS) emission and ROS-related protein damage indicating substantial alleviation of cellular oxidative stress. RNA-sequence data reveal the effects of MOTS-c treatment to potentially be exerted subtly across a number of mitochondrial parameters such as redox handling, mitochondrial integrity and OXPHOS efficiency, jointly indicating a mechanistic basis for the observed functional improvements in mitochondrial bioenergetics. Despite increased interstitial MOTS-c levels no change was observed in the arterio-venous difference during one-legged knee extensor exercise in humans. This suggests that SkM may not be the source of circulating MOTS-c in response to exercise.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"682-696"},"PeriodicalIF":8.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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