Gouthami Kuruvalli, Nagajyothi P C, Shekhawat Deepika, Santra Ayantika, Maity Subhasish, Surtineni Venkata Prasad, Arjunan Selvam, Reddy Vaddi Damodara, Shim Jaesool
Department of Biochemistry, REVA University, Rukmini Knowledge Park, Kattigenahalli, Yelahanka, Bangalore, 560064, Karnataka, India.
Biotechnology, REVA University, Rukmini Knowledge Park, Kattigenahalli, Yelahanka, Bangalore, 560064, Karnataka, India.
Mol Biol Rep. 2025 Sep 12;52(1):900. doi: 10.1007/s11033-025-10985-3.
Chronic alcohol consumption induces significant structural and functional impairments in hepatic mitochondria, primarily mediated through increased production of reactive oxygen and nitrogen species (ROS/RNS), leading to oxidative and nitrosative damage. The mitochondrial electron transport chain (ETC), especially complexes I, II, IV, and V, is a major target of such damage, resulting in diminished catalytic activities as demonstrated by decreased NADH dehydrogenase and cytochrome c oxidase activities in ethanol-fed rat models. Notably, succinate dehydrogenase (complex II) remains largely unaffected, consistent with prior studies. Peroxynitrite-mediated nitration of critical subunits further compromises ETC function, impairing oxidative phosphorylation and ATP synthesis. Ethanol-induced mitochondrial dysfunction also involves altered mitochondrial protein synthesis due to inhibited translation of mitochondrial-encoded polypeptides, disruption of nuclear-mitochondrial cross-talk, and increased proteolytic degradation of respiratory chain proteins. Additionally, ethanol exposure reduces cytochrome content, especially cytochrome a a3, exacerbating impaired electron transfer and respiratory capacity. Membrane transport processes are disrupted, as evidenced by altered Na⁺/K⁺-ATPase activity and compromised membrane fluidity, further impacting cellular homeostasis. Oxidative modifications to mitochondrial protein thiols, elevated protein carbonylation, and increased protein acetylation, particularly mediated by Sirt3 dysregulation, contribute to mitochondrial dysfunction. These post-translational modifications (PTMs) alter enzyme activity, protein stability, and mitochondrial signalling pathways. Cumulatively, these biochemical and molecular alterations compromise mitochondrial membrane polarization, β-oxidation, and ATP production, contributing to alcoholic liver disease pathogenesis. Our review elucidates multiple mechanistic facets of alcohol-induced mitochondrial injury, emphasizing the critical role of oxidative/nitrosative stress and PTMs in mitochondrial and hepatic cellular dysfunction.
长期饮酒会导致肝线粒体出现显著的结构和功能损伤，主要是通过活性氧和氮物种（ROS/RNS）生成增加介导的，从而导致氧化和亚硝化损伤。线粒体电子传递链（ETC），尤其是复合体I、II、IV和V，是此类损伤的主要靶点，导致催化活性降低，如在乙醇喂养的大鼠模型中NADH脱氢酶和细胞色素c氧化酶活性降低所证明的那样。值得注意的是，琥珀酸脱氢酶（复合体II）在很大程度上未受影响，这与先前的研究一致。过氧亚硝酸盐介导的关键亚基硝化进一步损害ETC功能，损害氧化磷酸化和ATP合成。乙醇诱导的线粒体功能障碍还涉及线粒体蛋白质合成改变，这是由于线粒体编码多肽的翻译受到抑制、核-线粒体相互作用的破坏以及呼吸链蛋白质的蛋白水解降解增加所致。此外，乙醇暴露会降低细胞色素含量，尤其是细胞色素aa3，加剧电子传递受损和呼吸能力下降。膜转运过程受到破坏，如Na⁺/K⁺-ATP酶活性改变和膜流动性受损所证明的那样，进一步影响细胞稳态。线粒体蛋白硫醇的氧化修饰、蛋白质羰基化升高和蛋白质乙酰化增加，特别是由Sirt3失调介导的，导致线粒体功能障碍。这些翻译后修饰（PTM）改变酶活性、蛋白质稳定性和线粒体信号通路。总的来说，这些生化和分子改变损害线粒体膜极化、β-氧化和ATP生成，促进酒精性肝病的发病机制。我们的综述阐明了酒精诱导的线粒体损伤的多个机制方面，强调了氧化/亚硝化应激和PTM在线粒体和肝细胞功能障碍中的关键作用。
