Mitochondrial complex I (NADH: ubiquinone oxidoreductase; CI) is central to the electron transport chain (ETC), oxidative phosphorylation, and ATP production in eukaryotes. CI is a multi-subunit complex with a complicated yet organized structure that optimally connects electron transfer with proton translocation and forms higher-order supercomplexes with other ETC complexes. Efforts to understand the molecular genetics, expression profile of subunits, and structure-function relationship of CI have increased over the years due to the direct role of the complex in human diseases. Although mutations in the nuclear and mitochondrial genes of CI and altered expression of subunits could potentially lower CI activity leading to mitochondrial dysfunction in many diseases, oxidative post-translational modifications (PTMs) have emerged as an important mechanism contributing to altered CI activity. These mainly include reversible and irreversible cysteine modifications, tyrosine nitration, carbonylation, and tryptophan oxidation that are generated following exposure to reactive oxygen species/reactive nitrogen species. Interestingly, oxidative PTMs could contribute either to CI damage, mitochondrial dysfunction, and ensuing cell death or a response mechanism with potential cytoprotective effects. This has also emerged as a promising field for structural biologists since analysis of PTMs could assist in understanding the structure-function relationship of the complex and correlate electron transfer mechanism with energy production. However, analysis of PTMs of CI and their contribution to CI function are incomplete in many physiological and pathological conditions. This review aims to highlight the role of oxidative PTMs in modulating CI activity with implications toward pathobiology of CNS diseases and novel therapeutics.
Keywords: Carbonylation; cysteine; nitration; nitrosation; oxidative stress; protein oxidation; thiols.