Antioxidants & redox signaling最新文献

{"title":"Sulforaphane Targets Multiple Pathological Processes in Friedreich Ataxia Patient-Induced Pluripotent Stem Cell-Derived Sensory Neurons.","authors":"Wenyao Yang, Bruce Thompson, Sara Miellet, Marnie Maddock, Marek Napierala, Mirella Dottori, Faith Kwa","doi":"10.1089/ars.2024.0756","DOIUrl":"https://doi.org/10.1089/ars.2024.0756","url":null,"abstract":"<p><p><b><i>Aims:</i></b> In Friedreich ataxia (FRDA), early motor discoordination stems from dysfunctional sensory neurons in the spinal cord driven by epigenetic dysregulation, frataxin (FXN) deficiency, oxidative stress, and inflammation. Omaveloxolone, a nuclear factor erythroid 2-related factor-2 (NRF2) inducer, is the only treatment available. In various chronic disease models, sulforaphane (SF) can target NRF2 and the above processes. This study compared the effects of SF with omaveloxolone and dimethyl fumarate (DMF) in sensory neurons generated from FRDA patient-induced pluripotent stem cells and their isogenic control. <b><i>Results:</i></b> The successful generation of the FRDA and isogenic control sensory neurons was confirmed by the positive expression of β-III TUBULIN, BRN3A, ISLET1, PERIPHERIN, and tropomyosin receptor kinase C. In comparison with the isogenic control, FRDA sensory neurons displayed an aberrant gene expression profile alike to that reported in patients. None of the drugs affected the viability of the isogenic control sensory neurons. SF treatment improved the viability of FRDA sensory neurons by up to 61% versus the untreated control. DMF treatment showed a modest 35% increase, while omaveloxolone lacked an effect. SF-treated FRDA sensory neurons demonstrated increased reduced glutathione/oxidized glutathione ratio and expression of FXN and redox markers, and a reduced expression of selected epigenetic enzymes and inflammatory cytokines, at the respective gene and protein levels. DMF and omaveloxolone treatments only modulated some of these biomarkers. <b><i>Innovation:</i></b> We revealed the therapeutic potential of SF and how it performs in comparison with omaveloxolone and DMF, in a physiologically and genetically relevant <i>in vitro</i> FRDA model. <b><i>Conclusion:</i></b> SF offers a multipronged approach to alleviating the different cellular events underlying FRDA. <i>Antioxid. Redox Signal.</i> 00, 000-000. [Figure: see text].</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126182","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}

{"title":"Small Molecules Targeting Non-Coding RNAs Regulating Ferroptosis: New Opportunities in Precision Cancer Therapy.","authors":"Junjing Zhang, Yan Wang, Joshua S Fleishman, Weihua Zheng, Hongquan Wang, Fanyu Meng, Yumin Wang","doi":"10.1089/ars.2024.0807","DOIUrl":"https://doi.org/10.1089/ars.2024.0807","url":null,"abstract":"<p><p>Ferroptosis, a distinct form of regulated cell death (RCD), has emerged as a promising approach for cancer treatment owing to its potential to inhibit tumor malignancy. Research indicates that non-coding RNAs (ncRNAs) regulate ferroptosis susceptibility in cancer cells through epigenetic modifications. ncRNAs play essential roles in cancer initiation, metastasis, and drug resistance. Findings indicate that small-molecule compounds (SMCs) target ncRNAs to regulate ferroptosis, providing new opportunities for precision cancer therapy. Therefore, this review aims to elucidate current molecular mechanisms underlying ncRNA-mediated ferroptosis regulation in cancer and investigate the potential of SMCs as therapeutic agents to modulate this process, offering a new strategy for precision in cancer treatment. This review also summarizes the innovative strategy of targeting ncRNAs with SMCs, a therapeutic approach for regulating ferroptosis and transforming the landscape of cancer treatment. Overall, it highlights a novel strategy for cancer therapy by pharmacologically targeting the ncRNA-ferroptosis axis with SMCs. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126181","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}

{"title":"Unraveling Ammonia-Induced Brain Endothelial Senescence: Role of miRNA-183-5p.","authors":"Karolina Orzeł-Gajowik, Krzysztof Milewski, Marta Obara-Michlewska, Aleksandra Ellert-Miklaszewska, Aneta Magiera, Karina Kwapiszewska, Magdalena Zielińska","doi":"10.1089/ars.2024.0784","DOIUrl":"https://doi.org/10.1089/ars.2024.0784","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Hyperammonemia, defined by elevated ammonia levels, may co-occur in various neurological disorders, but its effects on cerebrovascularity are not fully understood. This study aimed to investigate how hyperammonemia affects brain endothelial cells senescence and selected within <i>in silico</i> analysis micro RNA-183-5p in this process. <b><i>Results:</i></b> Reduction in cerebrovascular density in hyperammonemia-induced rats, similar to that seen in 12-month-old rats, using von Willebrand factor staining, was observed. MicroRNA (miRNA) profile analysis of the brain cortex and plasma identified miRNA-183-5p contributing to endothelial senescence. <i>In vitro</i> studies of ammonia-treated rat brain endothelial cell line 4 showed senescent features, including increased β-galactosidase activity, higher mRNA levels and fluorescence intensity of p16 and p21, and altered senescence-associated secretory phenotype. Additionally, the transfection of miRNA-183-5p mimic induced similar senescent characteristics in endothelial cells, whereas miRNA-183-5p mimic inhibition reversed some effects. <b><i>Innovation:</i></b> This study is the first to link hyperammonemia-induced cerebrovascular dysfunction with miRNA-183-5p, highlighting its role in promoting endothelial senescence. The findings suggest that miRNA-183-5p could be a target for therapeutic interventions, preventing ammonia-induced brain endothelial dysfunction. <b><i>Conclusion:</i></b> Hyperammonemia promotes brain endothelial cells senescence through miRNA-183-5p, reducing cerebrovascular density. This may contribute to cerebral dysfunction seen in hyperammonemia-associated neurological disorders. Targeting miRNA-183-5p could offer a novel therapeutic strategy to mitigate endothelial dysfunction and preserve brain health in hyperammonemia. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126094","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}

{"title":"Redox Differences Between Neurons and Astrocytes <i>In Vivo</i> in Ischemic Brain Tissues of Rodents.","authors":"Daria A Kotova, Aleksandra D Ivanova, Ilya V Kelmanson, Kseniia I Morozova, Yulia V Khramova, Maxim A Solotenkov, Evgeny A Stepanov, Aleksandr A Moshchenko, Alisa B Tiaglik, Anna A Fedotova, Anton V Zalygin, Vladimir A Oleinikov, Alexey G Katrukha, Alexey Semyanov, Vsevolod V Belousov, Andrei B Fedotov, Ilya V Fedotov, Nadezda A Brazhe, Dmitry S Bilan","doi":"10.1089/ars.2024.0876","DOIUrl":"https://doi.org/10.1089/ars.2024.0876","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Reactive oxygen species (ROS) are considered to play a key damaging role in brain during the development of ischemic stroke. To clarify how different ROS contribute to ischemic pathogenesis, innovative approaches for real-time <i>in vivo</i> detection of redox parameters are necessary. <b><i>Results:</i></b> Using highly sensitive genetically encoded biosensor HyPer7 and a fiber-optic neurointerface technology, we demonstrated that the level of hydrogen peroxide (H₂O₂) slowly increases in neurons and astrocytes of the ischemic area of the rat brain after middle cerebral artery occlusion during next 40 h; notably, in astrocytes the level is somewhat higher. Raman microspectroscopy in awake mice also revealed redox differences between mitochondria of neurons and astrocytes during acute ischemia caused by photothrombosis. Astrocytes demonstrated the overloading of the electron transport chain (ETC) with electrons after 1 h of ischemia, whereas neurons do not demonstrate changes in the amount of reduced electron carries. <b><i>Innovation and Conclusion:</i></b> The combination of novel <i>in vivo</i> approaches allows to detail redox events with spatiotemporal resolution. We demonstrated redox difference between neurons and astrocytes in damaged brain areas <i>in vivo</i>. An elevated loading of astrocytic ETC with electrons during the acute ischemia phase provides basis for the increased generation of superoxide anion radical (O₂^•-) with its following conversion to other reactive species. However, we observed increased H₂O₂ concentrations in astrocytes and neurons at later pathogenesis stages. During this period, ETC did not demonstrate an elevated loading with electrons, and therefore, increased H₂O₂ generation may be a phenomenon of secondary redox events. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092718","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}

{"title":"Exosomal miR-196a-5p Secreted by Bone Marrow Mesenchymal Stem Cells Inhibits Ferroptosis and Promotes Drug Resistance of Acute Myeloid Leukemia.","authors":"Bingjie Fan, Li Wang, Tianzhen Hu, Lin Zheng, Jishi Wang","doi":"10.1089/ars.2024.0882","DOIUrl":"https://doi.org/10.1089/ars.2024.0882","url":null,"abstract":"<p><p><b><i>Background:</i></b> Ferroptosis is a nonapoptotic type of cell death characterized by an increase in lipid reactive oxygen species (ROS). Acute myeloid leukemia (AML)-derived bone marrow mesenchymal stem cells (AML-BMSCs) support the progression and drug resistance of AML by secreting various bioactive substances, including exosomes. However, the role of BMSCs in regulating lipid metabolism and ferroptosis in AML remains unexplored. <b><i>Results:</i></b> Exosomes secreted by AML-BMSCs increased the expression of miR-196a-5p in AML cells. MiR-196a-5p promoted the proliferation of AML cells, reduced lipid ROS and ferroptosis, and was associated with poor prognosis in AML patients. Mechanistically, miR-196a-5p inhibited the expression level of neural precursor cell expressed developmentally down-regulated 4-like (NEDD4L). Co-immunoprecipitation (CO-IP) analysis showed that NEDD4L was bound to long-chain acyl-CoA synthetase (ACSL)3 and promoted ubiquitin-mediated degradation of ACSL3 protein. In addition, we also demonstrated that AML-BMSCs highly expressed Ras-associated binding protein 7A (RAB7A), which was associated with exosomal miR-196a-5p release. Importantly, cytarabine (Ara-C) activated the expression of RAB7A and promoted the secretion of exosomal miR-196a-5p, which weakened the ubiquitination of ACSL3 by NEDD4L, leading to ferroptosis inhibition and Ara-C resistance in AML. <b><i>Innovation:</i></b> This is the first time that exosomes secreted by BMSCs (BMSCs-exos) have been linked to ferroptosis in AML cells, thereby expanding our understanding of the mechanism of drug resistance in AML cells. High miR-196a-5p expression reduced lipid ROS levels and ferroptosis in AML cells by inhibiting NEDD4L-mediated ubiquitination of ACSL3. <b><i>Conclusion:</i></b> This study identified a new network through which BMSCs-exos regulate ferroptosis in AML cells. We combined BMSCs and AML cells to provide new ideas for drug research targeting exosome secretion and ferroptosis. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101030","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}

{"title":"Downregulation of the Zinc Transporter ZIP13 (Slc39a13) Leads to Ferroptosis by Inhibiting Mitochondrial Iron-Sulfur Cluster Biosynthesis and Induces Ischemia/Reperfusion Injury in Mouse Hearts.","authors":"Rui Zhang, Jiannan Wang, Qing Yang, Yonghao Yu, Xinxin Cheng, Zhelong Xu","doi":"10.1089/ars.2024.0815","DOIUrl":"https://doi.org/10.1089/ars.2024.0815","url":null,"abstract":"<p><p><b><i>Aims:</i></b> While ferroptosis is involved in the pathogenesis of myocardial ischemia/reperfusion (I/R) injury, the exact mechanism underlying the induction of ferroptosis by I/R remains elusive. Since downregulation of Zrt, Irt-like protein 13 (ZIP13) plays a role in I/R injury by targeting mitochondria, we hypothesized that ZIP13 downregulation during I/R leads to ferroptosis through a mitochondria-dependent mechanism. <b><i>Results:</i></b> ZIP13 cKO (cardiac-specific conditional knockout) induced ferroptosis and suppressed mitochondrial iron-sulfur cluster (ISC) biosynthesis. ZIP13 cKO also reduced glutathione levels as well as solute carrier family 7 member 11 (SLC7A11) expression. Moreover, cKO increased mitochondrial Fe²⁺ levels. Similar to the action of cKO, I/R led to ZIP13 downregulation, ferroptosis, mitochondrial Fe²⁺ accumulation, and suppression of ISC biosynthesis. In support, cKO of ZIP13 aggravated I/R-induced ferroptosis and mitochondrial Fe²⁺ accumulation. In contrast, ZIP13 overexpression prevented I/R-induced ferroptosis, mitochondrial Fe²⁺ accumulation, and suppression of ISC biosynthesis. Finally, ferrostatin-1, a ferroptosis inhibitor, alleviated I/R-induced ferroptosis as well as cardiac injury in cKO mice. <b><i>Innovation:</i></b> This study proposes a previously unknown mechanism by which ZIP13 downregulation contributes to ferroptosis in the setting of myocardial I/R. <b><i>Conclusions:</i></b> These findings highlight that ZIP13 downregulation at reperfusion triggers ferroptosis by suppressing the mitochondrial ISC biosynthesis followed by mitochondrial Fe²⁺ accumulation. Downregulation of SLC7A11 may also contribute to the action of ZIP13 downregulation. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101025","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}

{"title":"Cystathionine γ-Lyase Attenuates Vascular Smooth Muscle Cell Senescence via Foxm1-Gas1 Pathway to Mediate Arterial Stiffness.","authors":"Qian Lin, Changting Cui, Ying Zhao, Yuefeng Geng, Huimin Gao, Xiaodie Shao, Ling Cheng, Haitao Li, Bin Geng","doi":"10.1089/ars.2024.0602","DOIUrl":"10.1089/ars.2024.0602","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Arterial stiffness, a hallmark of vascular aging, significantly contributes to hypertension and impaired organ perfusion. Vascular smooth muscle cell (VSMC) dysfunction, particularly VSMC senescence and its interaction with stiffness, is crucial in the pathogenesis of arterial stiffness. Although hydrogen sulfide (H₂S) and its key enzyme cystathionine γ-lyase (CSE) are known to play roles in cardiovascular diseases, their effects on arterial stiffness are not well understood. <b><i>Methods & Results:</i></b> First, we observed a downregulation of CSE/H₂S in the aortic media during biological aging and angiotensin II (AngII)-induced aging. The VSMC-specific CSE knockout mice were created by loxp-cre (Tagln-cre) system and which exacerbated AngII-induced aortic aging and stiffness <i>in vivo</i> and VSMC senescence and stiffness <i>in vitro</i>. Conversely, the CSE agonist norswertianolin mitigated these effects. Next, we identified growth arrest-specific 1 (Gas1) as a crucial target of CSE/H₂S and found it to be a downstream target gene of forkhead box protein M1 (Foxm1). siRNA knockdown Foxm1 increased Gas1 transcription and reduced the protective effects of H₂S on VSMC senescence and stiffness. Finally, we demonstrated that CSE/H₂S sulfhydrates Foxm1 at the C210 site, regulating its nuclear translocation and activity, thus reducing VSMC senescence and stiffness. <b><i>Innovation:</i></b> Our findings highlight the protective role of CSE/H₂S in arterial stiffness, emphasizing the novel contributions of CSE, Gas1, and Foxm1 to VSMC senescence and stiffness. <b><i>Conclusion:</i></b> Endogenous CSE/H₂S in VSMCs reduces VSMC senescence and stiffness, thereby attenuating arterial stiffness and aging, partly through sulfhydration-mediated activation of Foxm1 and subsequent inhibition of Gas1 signaling pathways. <i>Antioxid. Redox Signal.</i> 42, 655-671.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"655-671"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124602","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}

{"title":"Angiotensin-Converting Enzyme-Dependent Intrarenal Angiotensin II Contributes to CTP: Phosphoethanolamine Cytidylyltransferase Downregulation, Mitochondrial Membranous Disruption, and Reactive Oxygen Species Overgeneration in Diabetic Tubulopathy.","authors":"Xia-Qing Li, Zhang-Zhang Xiao, Ke Ma, Xia-Yun Liu, Huan-Huan Liu, Bo Hu, Qian Zhao, Hong-Yue Li, Rui-Chang Chen, Yu Meng, Liang-Hong Yin","doi":"10.1089/ars.2024.0637","DOIUrl":"10.1089/ars.2024.0637","url":null,"abstract":"<p><p><b><i>Aims:</i></b> The limited therapeutic options for diabetic tubulopathy (DT) in early diabetic kidney disease (DKD) reflect the difficulty of targeting renal tubular compartment. While renin-angiotensin-aldosterone system (RAS) inhibitors are commonly utilized in the management of DKD, how intrarenal RAS contributes to diabetic tubular injury is not fully understood. Mitochondrial disruption and reactive oxygen species (ROS) overgeneration have been involved in diabetic tubular injury. Herein, we aim to test the hypothesis that angiotensin-converting enzyme (ACE)-dependent intrarenal angiotensin II (AngII) disrupts tubular mitochondrial membranous homeostasis and causes excessive ROS generation in DT. <b><i>Results:</i></b> Mice suffered from renal tubular mitochondrial disruption and ROS overgeneration following high-fat diet/streptozocin-type 2 diabetic induction. Intrarenal AngII generation is ACE-dependent in DT. Local AngII accumulation in renal tissues was achieved by intrarenal artery injection. ACE-dependent intrarenal AngII-treated mice exhibit markedly elevated levels of makers of tubular injury. CTP: Phosphoethanolamine cytidylyltransferase (PCYT2), the primary regulatory enzyme for the biosynthesis of phosphatidylethanolamine, was enriched in renal tubules according to single-cell RNA sequencing. ACE-dependent intrarenal AngII-induced tubular membranous disruption, ROS overgeneration, and PCYT2 downregulation. The diabetic ambiance deteriorated the detrimental effect of ACE-dependent intrarenal AngII on renal tubules. Captopril, the ACE inhibitor (ACEI), showed efficiency in partially ameliorating ACE-dependent intrarenal AngII-induced tubular deterioration pre- and post-diabetic induction. <b><i>Innovation and Conclusion:</i></b> This study uncovers a critical role of ACE-dependent intrarenal AngII in mitochondrial membranous disruption, ROS overgeneration, and PCYT2 deficiency in diabetic renal tubules, providing novel insight into DT pathogenesis and ACEI-combined therapeutic targets. <i>Antioxid. Redox Signal.</i> 42, 767-786.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"767-786"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574798","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}

{"title":"Exploring the Molecular Interplay Between Oxygen Transport, Cellular Oxygen Sensing, and Mitochondrial Respiration.","authors":"Sirsendu Jana, Abdu I Alayash","doi":"10.1089/ars.2023.0428","DOIUrl":"10.1089/ars.2023.0428","url":null,"abstract":"<p><p><b><i>Significance:</i></b> The mitochondria play a key role in maintaining oxygen homeostasis under normal oxygen tension (normoxia) and during oxygen deprivation (hypoxia). This is a critical balancing act between the oxygen content of the blood, the tissue oxygen sensing mechanisms, and the mitochondria, which ultimately consume most oxygen for energy production. <b><i>Recent Advances:</i></b> We describe the well-defined role of the mitochondria in oxygen metabolism with a special focus on the impact on blood physiology and pathophysiology. <b><i>Critical Issues:</i></b> Fundamental questions remain regarding the impact of mitochondrial responses to changes in overall blood oxygen content under normoxic and hypoxic states and in the case of impaired oxygen sensing in various cardiovascular and pulmonary complications including blood disorders involving hemolysis and hemoglobin toxicity, ischemia reperfusion, and even in COVID-19 disease. <b><i>Future Directions:</i></b> Understanding the nature of the crosstalk among normal homeostatic pathways, oxygen carrying by hemoglobin, utilization of oxygen by the mitochondrial respiratory chain machinery, and oxygen sensing by hypoxia-inducible factor proteins, may provide a target for future therapeutic interventions. <i>Antioxid. Redox Signal.</i> 42, 730-750.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"730-750"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021884","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}

{"title":"Succinate Activates Uncoupling Protein 2 to Suppress Neuroinflammation and Confer Protection Following Intracerebral Hemorrhage.","authors":"Yecheng Wang, Caiyun Huang, Xiaoying Wang, Rong Cheng, Xue Li, Jiahao Wang, Lu Zhang, Fuhao Li, Hao Wang, Xinyu Li, Yi Li, Yiqing Xia, Jian Cheng, Xiaofan Pan, Jia Jia, Guo-Dong Xiao","doi":"10.1089/ars.2024.0573","DOIUrl":"10.1089/ars.2024.0573","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Succinate, a metabolite in the tricarboxylic acid cycle, is increasingly recognized to play essential roles in inflammation by functioning either as an intracellular or extracellular signaling molecule. However, the role and mechanisms of succinate in inflammation remain elusive. Here, we investigated the mechanism underlying the effects of succinate on neuroinflammation in intracerebral hemorrhage (ICH) models. [Figure: see text] <b><i>Results:</i></b> We unexpectedly found that succinate robustly inhibited neuroinflammation and conferred protection following ICH. Mechanistically, the oxidation of succinate by succinate dehydrogenase (SDH) drove reverse electron transport (RET) at mitochondrial complex I, leading to mitochondrial superoxide production in microglia. Complex I-derived superoxides, in turn, activated uncoupling protein 2 (UCP2). By using mice with specific deletion of UCP2 in microglia/macrophages, we showed that UCP2 was needed for succinate to inhibit neuroinflammation, confer protection, and activate downstream 5'-adenosine monophosphate-activated protein kinase (AMPK) following ICH. Moreover, knockdown of SDH, complex I, or AMPK abolished the therapeutic effects of succinate following ICH. <b><i>Innovation and Conclusion:</i></b> We provide evidence that driving complex I RET to activate UCP2 is a novel mechanism of succinate-mediated intracellular signaling and a mechanism underlying the inhibition of neuroinflammation by succinate. <i>Antioxid. Redox Signal.</i> 42, 687-710.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"687-710"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124603","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}