Nicotinamide Riboside Attenuated Cell Damage Induced by the MT-ND4 (G11778A) Mutation

The mechanisms underlying cellular damage induced by the m.11778G > A variant in complex I of Leber Hereditary Optic Neuropathy (LHON) remain critically important. Currently, though no curative drug therapy is available for LHON, mitochondria-targeted therapies represent promising therapeutic avenues. Nicotinamide riboside (NR), a precursor to NAD+, enhances mitochondrial respiration and reduces oxidative stress, positioning it as a candidate for LHON treatment. To elucidate the specific effects of NR on cell death triggered by the R340H mutation, mitochondrial dysfunction was investigated in 661W photoreceptor cells expressing exogenous MT-ND4 (m.11778G > A). The study revealed that NR mitigated cell death and apoptosis in these cells under galactose conditions and ameliorated pattern ERG impairments in MT-ND4 mice. Mechanistically, NR treatment attenuated the reduction in oxygen consumption rate (OCR) and the increase in reactive oxygen species (ROS) levels in 661W cells carrying the R340H mutation. Furthermore, cells expressing MT-ND4 (m.11778G > A) exhibited decreased catalase (CAT) activity, superoxide dismutase (SOD) levels, and glutathione disulfide (GSSG), all of which were restored by NR administration. Collectively, these findings indicate that the MT-ND4 (m.11778G > A) mutation promotes cellular death through disrupting oxidative balance, as evidenced by impaired mitochondrial oxygen consumption, elevated oxidative products, and weakened antioxidant capacity. NR appears to confer rescue effects by restoring oxidative equilibrium, underscoring it as a potential therapeutic approach for LHON.