Redox Biology最新文献

{"title":"ZnR/GPR39 regulates hepatic insulin signaling, tunes liver bioenergetics and ROS production, and mitigates liver fibrosis and injury","authors":"Anil Khushalrao Shendge,&nbsp;Israel Sekler,&nbsp;Michal Hershfinkel","doi":"10.1016/j.redox.2024.103403","DOIUrl":"10.1016/j.redox.2024.103403","url":null,"abstract":"<div><div>Adequate supply of zinc is essential for hepatic function and its deficiency is associated with acute liver injury (ALI) and chronic nonalcoholic fatty liver disease (NAFLD). However, how zinc controls hepatic function is unknown. We found that the zinc sensitive ZnR/GPR39, a mediator of zinc signaling, enhances hepatic phosphorylation of ERK1/2, which is reduced in ZnR/GPR39 deficient livers. Surprisingly, livers from ZnR/GPR39 knockout (KO) mice exhibited elevated insulin receptor expression and downstream AKT activation. Moreover, ZnR/GPR39 KO mice had higher blood fasting glucose level, pronounced hepatic lipid accumulation, increased hepatocyte oxygen consumption rate (OCR) and reactive oxygen species (ROS) levels. These data suggest that ZnR/GPR39 modulates insulin receptor signaling, a major pathway in hepatic metabolism. Associated with the impaired signaling, ZnR/GPR39 KO livers exhibited increased tissue fibrosis, manifested by marked elevation of collagen expression, compared to wildtype (WT). Additionally, we found alteration of hepatocyte junctional proteins that was accompanied by increased macrophage infiltration and higher liver inflammation in ZnR/GPR39 KO mice. To determine the role of ZnR/GPR39 in ALI, we applied a mild LPS challenge that induced profound decrease in hepatic OCR, also leading to higher ROS generation in ZnR/GPR39 KO hepatocytes, but not in WT. We further found increased serum IL-2 and AST/ALT ratio only in ZnR/GPR39 KO mice. Our findings reveal a role of ZnR/GPR39 in controlling hepatic insulin receptor signaling and mitigating liver fibrosis and inflammation, thus underscoring the important role of ZnR/GPR39 in liver signaling and function.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"78 ","pages":"Article 103403"},"PeriodicalIF":10.7,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142606168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neutrophils with low production of reactive oxygen species are activated during immune priming and promote development of arthritis","authors":"Tao Chen ,&nbsp;Zhen Zhou ,&nbsp;Yi Liu ,&nbsp;Jiayi Xu ,&nbsp;Chenxi Zhu ,&nbsp;Rui Sun ,&nbsp;Huifang Hu ,&nbsp;Yan Liu ,&nbsp;Lunzhi Dai ,&nbsp;Rikard Holmdahl ,&nbsp;Martin Herrmann ,&nbsp;Lulu Zhang ,&nbsp;Luis E. Muñoz ,&nbsp;Liesu Meng ,&nbsp;Yi Zhao","doi":"10.1016/j.redox.2024.103401","DOIUrl":"10.1016/j.redox.2024.103401","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA) is an inflammatory autoimmune disease mediated by immune cell dysfunction for which there is no universally effective prevention and treatment strategy. As primary effector cells, neutrophils are important in the inflammatory joint attack during the development of RA. Here, we used single-cell sequencing technology to thoroughly analyze the phenotypic characteristics of bone marrow-derived neutrophils in type II collagen (COL2)-induced arthritis (CIA) models, including mice primed and boosted with COL2. We identified a subpopulation of neutrophils with high expression of neutrophil cytoplasmic factor 1 (NCF1) in primed mice, accompanied by a characteristic reactive oxygen species (ROS) response, and a decrease in <em>Ncf1</em> expression in boosted mice with the onset of arthritis. Furthermore, we found that after ROS reduction, arthritis occurred in primed mice but was attenuated in boosted mice. This bidirectional effect of ROS suggested a protective role of ROS during immune priming. Mechanistically, we combined functional assays and metabolomics identifying <em>Ncf1</em>-deficient neutrophils with enhanced migration, chemotactic receptor CXCR2 expression, inflammatory cytokine secretion, and Th1/Th17 differentiation. This alteration was mainly due to the metabolic reprogramming of <em>Ncf1</em>-deficient neutrophils from an energy supply pathway dominated by gluconeogenesis to an inflammatory immune pathway associated with the metabolism of histidine, glycine, serine, and threonine signaling, which in turn induced arthritis. In conclusion, we have systematically identified the functional and inflammatory phenotypic characteristics of neutrophils under ROS regulation, which provides a theoretical basis for understanding the pathogenesis of RA, to further improve prevention strategies and identify novel therapeutic targets.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"78 ","pages":"Article 103401"},"PeriodicalIF":10.7,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of nuclear receptor pregnane-X-receptor protects against abdominal aortic aneurysm by inhibiting oxidative stress","authors":"Zhi Shen ,&nbsp;Jinxi Wang ,&nbsp;Yifei Chen ,&nbsp;Peiliang Fang ,&nbsp;Ancai Yuan ,&nbsp;Alex F. Chen ,&nbsp;Xiaoxiang Yan ,&nbsp;Yuyan Lyu ,&nbsp;Jun Pu","doi":"10.1016/j.redox.2024.103397","DOIUrl":"10.1016/j.redox.2024.103397","url":null,"abstract":"<div><div>Abdominal aortic aneurysm (AAA) is a life-threatening condition, but effective medications to prevent its progression and rupture are currently lacking. The nuclear receptor pregnane-X-receptor (PXR) plays a crucial role in vascular homeostasis. However, the role of PXR in AAA development remains unknown. We first detected the PXR expression in human and murine AAA tissues by RT-qPCR and Western blot. To investigate the potential role of PXR in the development of AAA, we used adeno-associated virus-mediated overexpression of PXR and pharmacological activation of PXR by ginkgolide A (GA) in mouse AAA models induced by both angiotensin II (AngII) and calcium phosphate [Ca₃(PO₄)₂]. The underlying mechanism was further explored using RNA-sequencing and molecular biological analyses. We found a significant decrease in both mRNA and protein levels of PXR in both human and murine aortic smooth muscle cells from AAA tissues, accompanied with phenotypic switching of vascular smooth muscle cell and increased oxidative stress. PXR overexpression in abdominal aortas and GA treatment successfully suppressed AAA formation in both mouse AAA models. RNA-sequencing data revealed that PXR activation inhibited gamma-aminobutyric acid type A receptor subunit alpha3 (GABRA3) expression. Additional mechanistic studies identified that PXR suppressed AAA through mitigating GABRA3-induced reactive oxygen species (ROS) generation and subsequent phosphorylation of c-Jun N-terminal kinase (JNK). Interestingly, p-JNK was found to induce ubiquitin-proteasome degradation of PXR. In summary, our data unveiled, for the first time, the protective role of PXR against AAA pathogenesis by inhibiting oxidative stress. These findings suggested PXR as a promising therapeutic target for AAA.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"77 ","pages":"Article 103397"},"PeriodicalIF":10.7,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of nuclear receptor pregnane-X-receptor protects against abdominal aortic aneurysm by inhibiting oxidative stress.","authors":"Zhi Shen,Jinxi Wang,Yifei Chen,Peiliang Fang,Ancai Yuan,Alex F Chen,Xiaoxiang Yan,Yuyan Lyu,Jun Pu","doi":"10.1016/j.redox.2024.103397","DOIUrl":"https://doi.org/10.1016/j.redox.2024.103397","url":null,"abstract":"Abdominal aortic aneurysm (AAA) is a life-threatening condition, but effective medications to prevent its progression and rupture are currently lacking. The nuclear receptor pregnane-X-receptor (PXR) plays a crucial role in vascular homeostasis. However, the role of PXR in AAA development remains unknown. We first detected the PXR expression in human and murine AAA tissues by RT-qPCR and Western blot. To investigate the potential role of PXR in the development of AAA, we used adeno-associated virus-mediated overexpression of PXR and pharmacological activation of PXR by ginkgolide A (GA) in mouse AAA models induced by both angiotensin II (AngII) and calcium phosphate [Ca3(PO4)2]. The underlying mechanism was further explored using RNA-sequencing and molecular biological analyses. We found a significant decrease in both mRNA and protein levels of PXR in both human and murine aortic smooth muscle cells from AAA tissues, accompanied with phenotypic switching of vascular smooth muscle cell and increased oxidative stress. PXR overexpression in abdominal aortas and GA treatment successfully suppressed AAA formation in both mouse AAA models. RNA-sequencing data revealed that PXR activation inhibited gamma-aminobutyric acid type A receptor subunit alpha3 (GABRA3) expression. Additional mechanistic studies identified that PXR suppressed AAA through mitigating GABRA3-induced reactive oxygen species (ROS) generation and subsequent phosphorylation of c-Jun N-terminal kinase (JNK). Interestingly, p-JNK was found to induce ubiquitin-proteasome degradation of PXR. In summary, our data unveiled, for the first time, the protective role of PXR against AAA pathogenesis by inhibiting oxidative stress. These findings suggested PXR as a promising therapeutic target for AAA.","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"79 1","pages":"103397"},"PeriodicalIF":11.4,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486385","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":"Binding of α-synuclein to ACO2 promotes progressive mitochondrial dysfunction in Parkinson's disease models","authors":"Jie Jiao ,&nbsp;Ge Gao ,&nbsp;Junge Zhu ,&nbsp;Chaodong Wang ,&nbsp;Lei Liu ,&nbsp;Hui Yang","doi":"10.1016/j.redox.2024.103399","DOIUrl":"10.1016/j.redox.2024.103399","url":null,"abstract":"<div><div>The accumulation of α-synuclein (α-syn), a key protein in Parkinson's disease (PD), contributes to progressive neuronal damage associated with mitochondrial dysfunction and interactions with various proteins. However, the precise mechanism by which α-syn affects energy metabolism remains unclear. In our study, we used human α-syn (hα-syn) transgenic mice, which exhibit progressive neuronal decline. Through an immunoprecipitation assay specific to hα-syn, we identified an enzyme in the mitochondrial tricarboxylic acid (TCA) cycle as a binding partner—mitochondrial aconitase 2 (ACO2), which converts citrate to isocitrate. Hα-syn increasingly interacted with ACO2 in mitochondria as mice aged, correlating with a progressive decrease in ACO2 activity. The overexpression of ACO2 and the addition of isocitrate, a downstream metabolite of ACO2, were observed to alleviate hα-syn-induced mitochondrial dysfunction and cytotoxicity. Furthermore, we designed an interfering peptide to block the interaction between ACO2 and hα-syn, which showed therapeutic effects in reducing hα-syn toxicity <em>in vitro</em> and <em>in vivo</em>. Our research establishes a direct link between α-syn and the TCA cycle and identifies ACO2 as a promising therapeutic target for improving mitochondrial function and reducing α-syn neurotoxicity in PD.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"77 ","pages":"Article 103399"},"PeriodicalIF":10.7,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Binding of α-synuclein to ACO2 promotes progressive mitochondrial dysfunction in Parkinson's disease models.","authors":"Jie Jiao,Ge Gao,Junge Zhu,Chaodong Wang,Lei Liu,Hui Yang","doi":"10.1016/j.redox.2024.103399","DOIUrl":"https://doi.org/10.1016/j.redox.2024.103399","url":null,"abstract":"The accumulation of α-synuclein (α-syn), a key protein in Parkinson's disease (PD), contributes to progressive neuronal damage associated with mitochondrial dysfunction and interactions with various proteins. However, the precise mechanism by which α-syn affects energy metabolism remains unclear. In our study, we used human α-syn (hα-syn) transgenic mice, which exhibit progressive neuronal decline. Through an immunoprecipitation assay specific to hα-syn, we identified an enzyme in the mitochondrial tricarboxylic acid (TCA) cycle as a binding partner-mitochondrial aconitase 2 (ACO2), which converts citrate to isocitrate. Hα-syn increasingly interacted with ACO2 in mitochondria as mice aged, correlating with a progressive decrease in ACO2 activity. The overexpression of ACO2 and the addition of isocitrate, a downstream metabolite of ACO2, were observed to alleviate hα-syn-induced mitochondrial dysfunction and cytotoxicity. Furthermore, we designed an interfering peptide to block the interaction between ACO2 and hα-syn, which showed therapeutic effects in reducing hα-syn toxicity in vitro and in vivo. Our research establishes a direct link between α-syn and the TCA cycle and identifies ACO2 as a promising therapeutic target for improving mitochondrial function and reducing α-syn neurotoxicity in PD.","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"53 1","pages":"103399"},"PeriodicalIF":11.4,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486384","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":"LGR6 protects against myocardial ischemia-reperfusion injury via suppressing necroptosis","authors":"Mengmeng Zhao ,&nbsp;Zihui Zheng ,&nbsp;Jianfang Liu ,&nbsp;Yao Xu ,&nbsp;Jishou Zhang ,&nbsp;Shanshan Peng ,&nbsp;Juan-Juan Qin ,&nbsp;Jun Wan ,&nbsp;Menglong Wang","doi":"10.1016/j.redox.2024.103400","DOIUrl":"10.1016/j.redox.2024.103400","url":null,"abstract":"<div><div>Regulated necrosis (necroptosis) and apoptosis are important biological features of ischemia-reperfusion (I/R) injury. However, the molecular mechanisms underlying myocardial necroptosis remain elusive. Leucine rich repeat containing G protein-coupled receptor 6 (LGR6) has been reported to play important roles in various cardiovascular disease. In this study, we aimed to determine whether LGR6 suppresses I/R-induced myocardial necroptosis and the underlying molecular mechanisms. We generated LGR6 knockout mice and used ligation of left anterior descending coronary artery to produce an in vivo I/R model. The effects of LGR6 and its downstream molecules were subsequently identified using RNA sequencing and CHIP assays. We observed significantly downregulated LGR6 expression in hearts post myocardial I/R and cardiomyocytes post hypoxia and reoxygenation (HR). LGR6 deficiency promoted and LGR6 overexpression inhibited necroptosis and acute myocardial injury after I/R. Mechanistically, in vivo and in vitro experiments suggest that LGR6 regulates the expression of STAT2 and ZBP1 by activating the Wnt signaling pathway, thereby inhibiting cardiomyocyte necroptosis after HR. Inhibiting STAT2 and ZBP1 effectively alleviated the aggravating effect of LGR6 deficiency on myocardial necroptosis after I/R. Furthermore, activating LGR6 with RSPO3 also effectively protected mice from acute myocardial I/R injury. Our findings reveal that RSPO3-LGR6 axis downregulates the expression of STAT2 and ZBP1 through the Wnt signaling pathway, thereby inhibiting I/R-induced myocardial injury and necroptosis. Targeting the RSPO3-LGR6 axis may be a potential therapeutic strategy to treat myocardial I/R injury.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"78 ","pages":"Article 103400"},"PeriodicalIF":10.7,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NoxO1 regulates EGFR signaling by its interaction with Erbin","authors":"Dana Maureen Hebchen ,&nbsp;Tim Schader ,&nbsp;Manuela Spaeth ,&nbsp;Niklas Müller ,&nbsp;Johannes Graumann ,&nbsp;Katrin Schröder","doi":"10.1016/j.redox.2024.103396","DOIUrl":"10.1016/j.redox.2024.103396","url":null,"abstract":"<div><div>NADPH oxidase organizer 1 (NoxO1) is a scaffold cytoplasmic subunit of the reactive oxygen species (ROS) forming Nox1 complex and involved in angiogenesis, differentiation, and atherosclerosis.</div><div>We found that overexpression of NoxO1 without simultaneous overexpression of any other component of the active Nox1 complex inhibited EGF-induced wound closure and signaling, while NoxO1 KO yielded the opposite effect. Accordingly, we hypothesize NoxO1 to exert Nox1 independent functions.</div><div>Using the <em>BioID</em> technique, we identified ErbB2 interacting protein (Erbin) as novel interaction partner of NoxO1. Colocalization of NoxO1 with EGFR, as well as with Erbin validated this finding. EGF treatment interrupted colocalization of NoxO1 and EGFR. EGF mediated kinase activation was delayed in NoxO1 overexpressing cells, while knockout of NoxO1 had the opposite effect.</div><div>In conclusion, Erbin was identified as a novel NoxO1 interacting protein. Through the subsequent interaction of NoxO1 and EGFR, NoxO1 interferes with EGF signaling. The results of this study suggest a potential role of NoxO1 as an adaptor protein with functions beyond the well-established enabling of Nox1 mediated ROS formation.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"77 ","pages":"Article 103396"},"PeriodicalIF":10.7,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Promising tools into oxidative stress: A review of non-rodent model organisms","authors":"Yuhao Zhang,&nbsp;Yun Li,&nbsp;Tianyi Ren,&nbsp;Jin-ao Duan,&nbsp;Ping Xiao","doi":"10.1016/j.redox.2024.103402","DOIUrl":"10.1016/j.redox.2024.103402","url":null,"abstract":"<div><div>Oxidative stress is a crucial concept in redox biology, and significant progress has been made in recent years. Excessive levels of reactive oxygen species (ROS) can lead to oxidative damage, heightening vulnerability to various diseases. By contrast, ROS maintained within a moderate range plays a role in regulating normal physiological metabolism. Choosing suitable animal models in a complex research context is critical for enhancing research efficacy. While rodents are frequently utilized in medical experiments, they pose challenges such as high costs and ethical considerations. Alternatively, non-rodent model organisms like zebrafish, <em>Drosophila</em>, and <em>C. elegans</em> offer promising avenues into oxidative stress research. These organisms boast advantages such as their small size, high reproduction rate, availability for live imaging, and ease of gene manipulation. This review highlights advancements in the detection of oxidative stress using non-rodent models. The oxidative homeostasis regulatory pathway, Kelch‐like ECH‐associated protein 1-Nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2), is systematically reviewed alongside multiple regulation of Nrf2-centered pathways in different organisms. Ultimately, this review conducts a comprehensive comparative analysis of different model organisms and further explores the combination of novel techniques with non-rodents. This review aims to summarize state-of-the-art findings in oxidative stress research using non-rodents and to delineate future directions.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"77 ","pages":"Article 103402"},"PeriodicalIF":10.7,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142506860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diallyl disulfide alleviates hepatic steatosis by the conservative mechanism from fish to tetrapod: Augment Mfn2/Atgl-Mediated lipid droplet-mitochondria coupling","authors":"Ling-Jiao Wang ,&nbsp;Xiao-Hong Lai ,&nbsp;Zhi Luo ,&nbsp;Guang-Li Feng ,&nbsp;Yu-Feng Song","doi":"10.1016/j.redox.2024.103395","DOIUrl":"10.1016/j.redox.2024.103395","url":null,"abstract":"<div><div>Despite increasing evidences has highlighted the importance of mitochondria-lipid droplet (LD) coupling in maintaining lipid homeostasis, little progress in unraveling the role of mitochondria-LD coupling in hepatic lipid metabolism has been made. Additionally, diallyl disulfide (DADS), a garlic organosulfur compound, has been proposed to prevent hepatic steatosis; however, no studies have focused on the molecular mechanism to date. To address these gaps, this study investigated the systemic control mechanisms of mitochondria-LD coupling regulating hepatic lipid metabolism, and also explored their function in the process of DADS alleviating hepatic steatosis. To this end, an animal model of lipid metabolism, yellow catfish <em>Pelteobagrus fulvidraco</em> were fed four different diets (control, high-fat, DADS and high-fat + DADS diet) <em>in vivo</em> for 8 weeks; <em>in vitro</em> experiments were conducted to inhibit Mfn2/Atgl-mediated mitochondria-LD coupling in isolated hepatocytes. The key findings are: (1) the activations of hepatic LDs lipolysis and mitochondrial β-oxidation are likely the major drivers for DADS alleviating hepatic steatosis; (2) the underlying mechanism is that DADS enhances mitochondria-LD coupling by promoting the interaction between mitochondrion-localized Mfn2 with LD-localized Atgl, which facilitates the hepatic LDs lipolysis and the transfer of fatty acids (FAs) from LDs to mitochondria for subsequent β-oxidation; (3) Mfn2-mediated mitochondrial fusion facilitates mitochondria to form more PDM, which possess higher β-oxidation capacity in hepatocytes. Significantly, the present research unveils a previously undisclosed mechanism by which Mfn2/Atgl-mitochondria-LD coupling relieves hepatic LDs accumulation, which is a conserved strategy from fish to tetrapod. This study provides another dimension for mitochondria-LD coupling and opens up new avenues for the therapeutic interventions in hepatic steatosis.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"77 ","pages":"Article 103395"},"PeriodicalIF":10.7,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142506857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}