Comprehensive review on alcohol-induced protein modifications in hepatic mitochondrial membranes and their functional implications.

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.