LHON: A look into nuclear and environmental factors; What is “sufficient”?

Abstract

PurposeIn Leber's Hereditary Optic Neuropathy (LHON) mutations of the mtDNA, are necessary but not sufficient for visual loss. We studied nuclear/environmental interactions in patients and in the Wallace LHON mouse model, to consider what is “sufficient”. The LHON mutation causes a modest decrease in ATP production, but a large increase in ROS production. Nuclear genetic and environmental factors may play upon these factorsMethodsWe noted in the data of Kirkman et al (Brain 2009) that heavy smoking mitigated visual loss by delaying disease onset. We reproduced these peculiar results (Carelli et al, Brain 2013). We also studied the ND6 mutant Wallace mouse model of LHON. 30 mice of 12 groups were sacrificed at 23 months including ND6 mutant vs ND6 wildtype and nicotinamide nucleotide transhydrogenase‐NNT +/+ vs ‐/‐ (NNT deletion), under different environments of air and smoke. 10 experiments compared the axonal nerve fiber spectrums.ResultsIn our patient pedigrees, heavy smoking also mitigated visual loss, but we saw in this, the existence of two subtypes of LHON. Type I, with an abrupt and severe loss of vision in the teens, was characterized by severe losses of both structure and function. Type II occured decades later with a more insidious onset, with less structural than functional loss. Type II patients were more likely to smoke. In the mice, we found the predominant loss of small fibers in NNT −/− mice carrying the ND6 mutation which were exposed to smoke.ConclusionsBoth nuclear modifiers and environmental factors in combination with LHON mutations can lead to vision loss. NNT is a transhydrogenase that couples hydride transfer from NAD(H) to NADP(+) and proton translocation across the inner mitochondrial membrane. NNT is potentially an important nuclear modifying gene for LHON.