Redox Biology最新文献

{"title":"Enhancing microglial antioxidant capacity via the ascorbate transporter SVCT2 delays onset and modifies disease progression in mouse models of Alzheimer's disease","authors":"Camila C. Portugal ,&nbsp;Evelyn C.S. Santos ,&nbsp;Ana Monteiro-Pacheco ,&nbsp;Sara Costa-Pinto ,&nbsp;Tiago O. Almeida ,&nbsp;Joana Tedim-Moreira ,&nbsp;Dora Gavin ,&nbsp;Teresa Canedo ,&nbsp;Fabiana Oliveira ,&nbsp;Isabel Cardoso ,&nbsp;Teresa Summavielle ,&nbsp;Sandra H. Vaz ,&nbsp;Renato Socodato ,&nbsp;João B. Relvas","doi":"10.1016/j.redox.2025.103851","DOIUrl":"10.1016/j.redox.2025.103851","url":null,"abstract":"<div><div>Despite clear evidence that vitamin C levels are depleted in the brains of Alzheimer's disease (AD) patients, dietary supplementation has consistently failed in clinical trials, suggesting a critical bottleneck not in systemic supply, but in its transport into brain cells. Here, we identify this bottleneck as a progressive downregulation of the ascorbate transporter, Slc23a2, also known as SVCT2, in microglia. Then we hypothesized that bypassing this cellular deficiency via targeted SVCT2 overexpression in microglia could either prevent the onset of pathology or rescue established functional deficits. Indeed, overexpressing SVCT2 in microglia before disease onset in 5xFAD mice triggered a profound redox reprogramming, resulting in a unique \"hybrid\" neuroprotective microglial phenotype that co-expressed both homeostatic and disease-associated markers. Functionally, this leads to decreased amyloid plaque burden and strengthens the synaptic bioenergetic capacity, which consequently prevents the development of synaptic and memory deficits. Strikingly, when employed after disease establishment, SVCT2 overexpression rescued synaptic plasticity and memory performance despite not affecting the existing amyloid burden. This rescue was driven by changes in the microglial secretory pathways. Collectively, these findings resolve a long-standing clinical paradox by establishing that neuroprotection depends not on systemic vitamin C intake but on the brain's cellular uptake machinery. This offers a mechanistic explanation for the failure of dietary supplementation in AD and identifies SVCT2 as a promising therapeutic target against the neurodegenerative process in AD.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103851"},"PeriodicalIF":11.9,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144988380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Redox compartmentalization drives functional heterogeneity of mature insulin secretory vesicles in pancreatic β-cells","authors":"Lu Zhuang ,&nbsp;Yuwei Zhao ,&nbsp;Qikai Qin ,&nbsp;Kejia Xiong ,&nbsp;Zhen Qian ,&nbsp;Yan Liu","doi":"10.1016/j.redox.2025.103847","DOIUrl":"10.1016/j.redox.2025.103847","url":null,"abstract":"<div><div>Pancreatic β-cell function requires precise regulation of insulin secretory vesicles (ISVs), yet the redox heterogeneity within mature ISVs remains poorly defined. Here, we implement a novel oxidation-sensing system using NPY-fused DsRed1-E5 (Timer) targeted to mature ISVs in INS-1E and human Endoc-βH5 β-cell models. Leveraging Timer's oxidative color transition from green (Low-oxidative) to yellow-red (High-oxidative), supported by independent measurements using the established redox sensor Grx1-roGFP2, we resolve distinct ISV subpopulations. Strikingly, Krebs-Ringer Bicarbonate HEPES (KRBH) Buffer treatment amplified ISV redox heterogeneity through increasing cytosolic oxidation. Factor screening identified glutamine deprivation as the principal driver of this diversification. Spatial analysis revealed Low-oxidative ISVs predominantly docked peripherally (0–1 μm from plasma membrane), while High-oxidative ISVs localized deeper (&gt;1 μm) and exhibited 1.7-fold higher mobility. TIRF microscopy and volumetric imaging both demonstrated superior glucose-responsive secretion from Low-oxidative ISVs during both first and second phases of glucose-stimulated insulin release. Lysotracker co-localization showed High-oxidative ISVs were preferentially targeted for lysosomal degradation (2.3-fold higher association). These findings establish an oxidation-based taxonomy for mature ISVs, linking redox states to distinct functional fates: secretion-competent Low-oxidative vesicles versus degradation-prone High-oxidative vesicles, redefining ISV heterogeneity as a fundamental organizational principle in β-cell physiology and its dysregulation in metabolic stress.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103847"},"PeriodicalIF":11.9,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144925536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms, therapeutic uses, and developmental perspectives of redox-active thiomolybdates","authors":"Yihan Wu ,&nbsp;Khalid S. Alotaibi ,&nbsp;Kevin Yu ,&nbsp;Tom Durham ,&nbsp;Felipe Dal-Pizzol ,&nbsp;Mervyn Singer ,&nbsp;Alex Dyson","doi":"10.1016/j.redox.2025.103846","DOIUrl":"10.1016/j.redox.2025.103846","url":null,"abstract":"<div><div>Redox-active, copper-chelating thiomolybdates are a family of metal-based therapeutics used to treat copper toxicity in animals and Wilson's disease in humans, and studied in other indications including cancer, inflammatory and fibrotic conditions. Thiomolybdates act through multiple mechanisms including copper chelation, redox regulation (e.g., superoxide dismutase inhibition), and modulation of inflammation. We and others have also identified thiomolybdates as slow-release sulfide donors that inhibit mitochondrial respiration, limit mitochondrial reactive oxygen species (ROS) production, augment antioxidant reserve capacity, and confer organ- and whole-body protection in non-clinical models of reperfusion injury. Here we review the rich history of the thiomolybdate drug class, focusing on their activity across multiple pathologies, utility in non-clinical and clinical settings, accepted and proposed mechanisms of action, developmental perspectives, and limitations. Context-specific use of thiomolybdates support their development as either first-in-class or next generation therapeutics across several disease areas. Dosing and route of administration differentiate the utility of thiomolybdates as either copper chelators (oral administration over several weeks) or sulfide donors (acute intravenous use). Further work is however required to understand the impact of both opposing and additive mechanisms of action. Examples include reduction of ROS generation versus superoxide dismutase inhibition in oxidative pathologies, and the opposing angiogenic effects of copper chelation and sulfide bioavailability in the tumor microenvironment.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103846"},"PeriodicalIF":11.9,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144931780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metastatic breast cancer cells are vulnerable to fatty acid oxidation inhibition through DDX3-DRP1-mediated mitochondrial plasticity","authors":"Wen-Jing Hsu ,&nbsp;Ming-Chien Hsu ,&nbsp;Cheng-Ying Chu ,&nbsp;Yu-Cheng Lee ,&nbsp;Ching-Chieh Yang ,&nbsp;Zei-Wei Liu ,&nbsp;Chi-Ching Lee ,&nbsp;Yang-Sen Lin ,&nbsp;Cheng-Wei Lin","doi":"10.1016/j.redox.2025.103845","DOIUrl":"10.1016/j.redox.2025.103845","url":null,"abstract":"<div><div>Metastatic tumor cells exhibit distinct metabolic flexibility in overcoming different microenvironmental obstacles and thriving in a secondary organ; thus, metabolic vulnerabilities can potentially be targeted. It was reported that mitochondrial biogenesis and dynamics play crucial roles in disseminated tumor cells satisfying their energy demands and metabolic plasticity. However, the detailed molecular mechanism by which mitochondrial dynamics promotes tumor metastasis is still unclear. Herein, we identified that metastatic breast cancer cells exhibited increased lipid contents in mitochondria and promoted a metabolic shift towards fatty acid oxidation (FAO). The increased FAO was accompanied by promotion of mitochondrial fission. Mechanistically, we found that upregulation of DEAD-box polypeptide 3, X-linked (DDX3) promoted mitochondrial fission and facilitated FAO. Suppression of DDX3 diminished FAO and elicited mitochondrial oxidative stress in metastatic tumor cells. Moreover, DDX3 mediated dynamin-related protein 1 (DRP1) phosphorylation at S616 through collaborating with cyclin-dependent kinase 1 (CDK1). Inhibition of the DDX3-DRP1-CDK1 axis reduced cancer stemness properties and tumor metastasis. Our findings indicate that DDX3 modulates mitochondrial plasticity to drive metabolic adaptation in breast tumor metastasis. DDX3 provides a potential diagnostic biomarker and therapeutic vulnerability through which cancer metabolism can be targeted.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103845"},"PeriodicalIF":11.9,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144907991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Strand-specific quantification of 8-oxo-dG and apurinic sites via Ligation-Dependent Probe Amplification (LPA)","authors":"Antonella Romano ,&nbsp;Antonia Feola ,&nbsp;Valentina Morgera ,&nbsp;Alfonso Tramontano ,&nbsp;Samantha Messina ,&nbsp;Daniel Gackowski ,&nbsp;Ewelina Zarakowska ,&nbsp;Ryszard Olinski ,&nbsp;Vittorio Enrico Avvedimento ,&nbsp;Candida Zuchegna ,&nbsp;Antonio Porcellini ,&nbsp;Antonio Pezone","doi":"10.1016/j.redox.2025.103842","DOIUrl":"10.1016/j.redox.2025.103842","url":null,"abstract":"<div><div>Oxidative DNA damage, characterized by the prominent lesion 8-oxo-7,8-dihydroguanine (8-oxo-dG), is linked to mutagenesis and genome instability. Accurately mapping these lesions with strand specificity and high resolution remains a major challenge, limiting our understanding of damage dynamics during transcription and repair. Here, we introduce a novel, highly sensitive ligation-dependent probe amplification (LPA) method that enables quantitative, strand-specific analysis of 8-oxo-dG and apurinic (AP) sites at single-nucleotide resolution. Our technique uses enzymatic digestion, highly selective ligation, and quantitative PCR to distinguish damaged from intact DNA strands, offering detailed insight into lesion localization and repair kinetics. When applied to estrogen-stimulated breast cancer cells, LPA reveals asymmetric, strand-specific guanine oxidation during transcriptional activation, characterized by rapid repair of the transcribed strand and more persistent damage on the non-transcribed strand. Our findings show that oxidative lesions are dynamically regulated by biological stimuli, reflecting a finely tuned balance between repair and damage buildup. This LPA approach is a powerful tool for exploring the complex relationship among redox signaling, DNA damage, and transcription regulation, furthering our understanding of redox-driven genome modulation in health and disease.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103842"},"PeriodicalIF":11.9,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144893130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uncovering a novel role of nAChRs in oxidative stress-mediated vascular dysfunction in COPD","authors":"Rosa Andreu-Martínez ,&nbsp;Onofre Munar-Rubert ,&nbsp;Jorge Rodríguez-Pérez ,&nbsp;Noelia López ,&nbsp;Bianca Barreira ,&nbsp;Laura Sánchez-Carretero ,&nbsp;Adele Cardeñosa ,&nbsp;Ana Marcos-Jiménez ,&nbsp;Luis Gandía ,&nbsp;Ramón Moreno-Balsalobre ,&nbsp;Héctor Milián ,&nbsp;Francisco Pérez-Vizcaíno ,&nbsp;Edgar Fernández-Malavé ,&nbsp;Germán Peces-Barba ,&nbsp;Cecilia Muñoz-Calleja ,&nbsp;Ángel Cogolludo ,&nbsp;María J. Calzada","doi":"10.1016/j.redox.2025.103838","DOIUrl":"10.1016/j.redox.2025.103838","url":null,"abstract":"<div><div>Tobacco smoke is the main risk factor for the development of chronic obstructive pulmonary disease (COPD). Despite current therapies alleviate symptoms there are limitations in the efficacy of treatments to curb its cardiovascular morbidities, particularly vascular dysfunction and the development of pulmonary hypertension. Our previous studies demonstrate that cigarette smoke directly contributes to pulmonary arterial dysfunction. Nevertheless, a further characterization of the molecular basis involved is needed for more effective targeted treatment. We have performed <em>in vitro</em> analysis with human pulmonary artery smooth muscle cells (hPASMC) challenged with cigarette smoke extract, and <em>in vivo</em> approaches of tobacco exposure in murine models and transgenic mice. Furthermore, we extended our analysis to include hPASMCs from COPD patients compared to non-COPD individuals, as well as pulmonary arteries from human tissue samples. These approaches allowed us to explore the molecular pathways contributing to the harmful effects from oxidative stress, calcium dysregulation and disruptions to the contractile machinery of pulmonary artery smooth muscle cells. Interestingly, these effects were triggered by the activation of nicotinic acetylcholine receptors (nAChRs) in these cells. Additionally, we demonstrated that nAChR antagonists or α7 nAChR deletion in a murine model effectively protected pulmonary artery function from damage. Most importantly, α7 nAChR expression in pulmonary arteries of COPD patients rose with disease severity and showed an inverse correlation with respiratory function. These findings have important clinical implications, indicating that nAChR-targeted tailored antagonists could be a promising therapeutic strategy for COPD-related vascular dysfunction.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103838"},"PeriodicalIF":11.9,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144923959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating particles carotenoids are associated with rehabilitation recovery in Parkinson's disease","authors":"Alice Gualerzi ,&nbsp;Martina Gerli ,&nbsp;Aurora Mangolini ,&nbsp;Silvia Picciolini ,&nbsp;Francesca Rodà ,&nbsp;Valentina Mangolini ,&nbsp;Stefano Doronzio ,&nbsp;Diego Longo ,&nbsp;Giulio Cherubini ,&nbsp;Cristina Polito ,&nbsp;Chiara De Santis ,&nbsp;Silvia Ramat ,&nbsp;Francesca Cecchi ,&nbsp;Gemma Lombardi ,&nbsp;Marzia Bedoni","doi":"10.1016/j.redox.2025.103841","DOIUrl":"10.1016/j.redox.2025.103841","url":null,"abstract":"<div><div>Circulating nanoparticles include Extracellular Vesicles (EVs) and other circulating EV-like particles that are known mediators of the trafficking of pathologic proteins associated with Parkinson's disease (PD) progression as well as of products of the oxidative damage that characterizes the disease. In the framework of the VIRTREAD-PD trial protocol, circulating particles were isolated from the serum of 30 subjects with PD before and after an intensive rehabilitation program using a treadmill. Raman spectroscopy was used to verify modifications in the biochemistry of circulating particles and proved that an intensive motor rehabilitation program could affect the molecular composition of EV-like particles in the blood of people with PD (pwPD). Analysis performed before and after 8 weeks of intensive rehabilitation demonstrate significant changes in the biomolecules associated with EV-like particles and in carotenoid content. The presence of antioxidants linked to circulating particles was proved to be informative for the profiling of pwPD at admission and prognostic of the rehabilitation recovery.</div><div>In conclusion, our data support the hypothesis that circulating particles have a dual role in PD, both in the neurodegenerative processes and in the response to rehabilitation. Besides, the Raman fingerprint and the spectral signature of carotenoids can represent measurable biomarkers of rehabilitation.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103841"},"PeriodicalIF":11.9,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of CISD2 as a protective strategy against doxorubicin-induced cardiotoxicity","authors":"Yi-Ju Chou ,&nbsp;Chi-Hsiao Yeh ,&nbsp;Chian-Feng Chen ,&nbsp;Chi-Jen Lo ,&nbsp;Jian-Hsin Yang ,&nbsp;Wen-Tai Chiu ,&nbsp;Cheng-Heng Kao ,&nbsp;Tsai-Yu Tzeng ,&nbsp;Zhao-Qing Shen ,&nbsp;Chien-Yi Tung ,&nbsp;Chung-Kuang Lu ,&nbsp;Mei-Ling Cheng ,&nbsp;Patrick C.H. Hsieh ,&nbsp;Shu-Ling Fu ,&nbsp;Ting-Fen Tsai","doi":"10.1016/j.redox.2025.103840","DOIUrl":"10.1016/j.redox.2025.103840","url":null,"abstract":"<div><h3>Background</h3><div>Cardiotoxicity of doxorubicin, a chemotherapy medication, remains the most dangerous side effect. CISD2 plays a critical role during cardiac aging.</div></div><div><h3>Objectives</h3><div>We use a potent CISD2 activator, hesperetin, to ameliorate doxorubicin-induced cardiotoxicity by upregulating CISD2 in mice.</div></div><div><h3>Methods</h3><div>Two animal models, an acute and a tumor-bearing doxorubicin-induced cardiotoxicity model, were used in this study. Both genetic and pharmacological approaches were employed. Transgenic mice and a potent CISD2 activator, hesperetin, were utilized to ameliorate doxorubicin-induced cardiotoxicity by upregulating CISD2 expression in mice. Additionally, a human-derived iPSC system was used to provide human-relevant evidence. Comprehensive biological, histological, transcriptomic, and metabolomic analyses were conducted.</div></div><div><h3>Results</h3><div>Five findings are pinpointed. Firstly, doxorubicin suppresses Cisd2 expression resulting in cardiac electromechanical dysfunction. Intriguingly, transgenic overexpression of Cisd2 mitigates doxorubicin-induced cardiotoxicity. Secondly, hesperetin effectively sustains a high level of Cisd2 and improves cardiac function in a Cisd2-dependent manner after doxorubicin treatment. Importantly, hesperetin doesn't influence the anti-cancer efficacy of doxorubicin. Thirdly, doxorubicin downregulates the transcription of CISD2 by decreasing the expression of two transcription regulators, TAF1 and TCF12. Fourthly, analysis of transcriptomic and metabolomic datasets reveals that hesperetin protects the heart via a network connecting glucose, fatty acids and amino acids metabolism, thereby ensuring a sufficient energy supply. Additionally, hesperetin improves antioxidation capacity via reinstating the pentose phosphate and glutathione pathways. Finally, in human iPSC-derived cardiomyocytes, hesperetin significantly upregulates CISD2 and protects the cells from doxorubicin-induced toxicity and functional damage.</div></div><div><h3>Conclusions</h3><div>Our results highlight the potential utility of Cisd2 and its activator hesperetin in chemotherapy involving doxorubicin.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103840"},"PeriodicalIF":11.9,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PGC-1α-mediated mitochondrial homeostasis imbalance aggravated gingival lesions of diabetic periodontitis by disrupting ECM remodeling of human gingival fibroblast","authors":"Junling Huang ,&nbsp;Yi Li ,&nbsp;Qingyuan Ye ,&nbsp;Rui Li ,&nbsp;Yazheng Wang ,&nbsp;Qintao Wang ,&nbsp;Jinjin Wang","doi":"10.1016/j.redox.2025.103829","DOIUrl":"10.1016/j.redox.2025.103829","url":null,"abstract":"<div><div>Diabetic periodontitis (DP) usually has more severe clinical symptoms compared with chronic periodontitis (CP), especially the worsened gingival lesions. Mitochondrial homeostasis plays an important role in both diabetes and periodontitis, and some studies have already confirmed its role in DP. However, there are few reports on whether mitochondrial homeostasis is involved in regulating DP gingival lesions. In this study, we focused on the pathological changes of the gingival connective tissues from DP and identified the extracellular matrix (ECM) pathway as the key regulatory pathway. Additionally, we found that the pathological changes in DP gingiva were accompanied by significant alterations in the morphology and structure of cellular mitochondria. We discovered that the regulatory molecule PGC-1α related to mitochondrial quality control (MQC) was significantly downregulated in DP group through RNA sequencing. Furthermore, by using high glucose and LPS co-stimulation to simulate DP environment in vitro, we confirmed the changes in ECM synthesis and remodeling of human gingival fibroblasts (HGFs), accompanied with the abnormal mitochondrial morphology, structure and function, including the presence of internal vacuolation, the increased area and perimeter, the loss of cristae, as well as the increased mtROS, the decreased ATP, mitochondrial membrane potential, and the mtDNA copy number, and even the reduced number of mitochondria in HGFs, which suggesting the changes of mitochondrial homeostasis. Moreover, we verified that upregulating PGC-1α could reverse the above phenomena in HGFs. Finally, periodontal injection of PGC-1α agonists (ZLN005) was found to ameliorate the abnormal ECM synthesis and remodeling by improving mitochondrial homeostasis in DP rats, demonstrating a significant therapeutic effect on DP gingival lesions and moderating the progression of DP. In conclusion, our study proposed the possible therapeutic effect of PGC-1α-mediated mitochondrial homeostasis in the aggravated gingival lesions of DP, providing new ideas for the clinical treatment of DP.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103829"},"PeriodicalIF":11.9,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired xCT-mediated cystine uptake drives serine and proline metabolic reprogramming and mitochondrial fission in skeletal muscle cells","authors":"Michel N. Kanaan ,&nbsp;Charbel Y. Karam ,&nbsp;Luke S. Kennedy ,&nbsp;Chantal A. Pileggi ,&nbsp;Lauren Hamilton ,&nbsp;Miroslava Cuperlovic-Culf ,&nbsp;Mary-Ellen Harper","doi":"10.1016/j.redox.2025.103839","DOIUrl":"10.1016/j.redox.2025.103839","url":null,"abstract":"<div><div>Muscle satellite cell (MuSC) proliferation is tightly regulated by redox homeostasis and nutrient availability, which are often disrupted in muscular pathologies. Beyond its role in maintaining cellular redox homeostasis, this study identified a key metabolic role for cystine/glutamate antiporter xCT in proliferating MuSCs. We investigated the impact of impaired xCT-mediated cystine import in Slc7a11^sut/sut MuSCs isolated from mice that harbor a mutation in the <em>SLC7A11</em> gene, which encodes xCT. We used complementary approaches to study how disrupted cystine import affects glutathione (GSH) redox, cellular bioenergetics, mitochondrial dynamics, and metabolism. Oxygen consumption rates of Slc7a11^sut/sut MuSCs were lower, indicative of compromised mitochondrial oxidative capacity. This was accompanied by a fragmented mitochondrial network associated with OPA1 cleavage and redox-sensitive DRP1 oligomerization. Metabolomic profiling revealed a distinct metabolic signature in Slc7a11^sut/sut MuSCs, manifested by major differences in BCAAs, pyrimidines, cysteine, methionine, and GSH. Despite lower overall bioenergetic flux, stable-isotope tracing analyses (SITA) showed that xCT deficiency increased glucose uptake, channeling glucose-derived carbons into <em>de novo</em> serine biosynthesis to fuel cysteine production via the transsulfuration pathway, partially compensating for disrupted GSH redox. Furthermore, xCT deficiency triggered upregulated pyrroline-5-carboxylate synthase (P5CS)-mediated proline reductive biosynthesis. By directing glutamate into proline synthesis, MuSCs apparently downregulate oxidative phosphorylation (OXPHOS) and regulate intracellular glutamate levels in response to impaired cystine/glutamate antiporter function. Our findings highlight the roles of xCT in regulating redox balance and metabolic reprogramming in proliferating MuSCs, providing insights that may inform therapeutic strategies for muscular and redox-related pathologies.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103839"},"PeriodicalIF":11.9,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}