ND6 encodes a core subunit of mitochondrial Complex I (NADH dehydrogenase), catalyzing electron transfer from NADH through the respiratory chain with ubiquinone as the electron acceptor, and is essential for Complex I catalytic activity and assembly. ND6 dysfunction impairs oxidative phosphorylation and ATP production, triggering secondary pathology across multiple tissues. In hepatic mitochondria, ND6 transcript levels are primarily decreased in obese and type 2 diabetes populations through hypermethylation-mediated silencing, and knockdown of hepatic ND6 impairs mitochondrial function and induces systemic insulin resistance 1. ND6 mutations cause Leber hereditary optic neuropathy (LHON), a maternally inherited retinal dystrophy in which the m.14484T>C variant causes retinal ganglion cell death through Complex I deficiency and increased reactive oxygen species 23. Emerging therapeutic approaches include nuclear-encoded ND6 transgene delivery via adeno-associated viral vectors, which restores Complex I assembly and reduces ROS-induced apoptosis in LHON models 24, and vitamin A supplementation, which alleviates ND6 mutation-induced visual dysfunction by correcting mitochondrial morphology and vitamin A metabolism 3. For insulin resistance and metabolic disorders, targeting hepatic DNA methyltransferase 1 to preserve ND6 expression represents a preventive strategy.