mt-Nd2a suppresses reactive oxygen species production by mitochondrial complexes I and III.

Reactive oxygen species play a critical role in the pathogenesis of human diseases. A cytosine to adenine transversion in the mitochondrially encoded NADH dehydrogenase subunit 2 (mt-ND2, human; mt-Nd2, mouse) gene results in resistance against type 1 diabetes and several additional conditions. Our previous studies have demonstrated that the adenine-containing allele (mt-Nd2(a)) is also strongly associated with resistance against type 1 diabetes in mice. In this report we have confirmed that the cytosine-containing allele (mt-Nd2(c)) results in elevated mitochondrial production. Using inhibitors of the electron transport chain, we show that when in combination with nuclear genes from the alloxan-resistant (ALR) strain, mt-Nd2(c) increases duanyu1670 from complex III. Furthermore, by using alamethicin-permeabilized mitochondria, we measured a significant increase in electron transport chain-dependent duanyu1670 production from all mt-Nd2(c)-encoding strains including ALR.mt(NOD), non-obese diabetic (NOD), and C57BL/6 (B6). Studies employing alamethicin and inhibitors were able to again localize the heightened duanyu1670 production in ALR.mt(NOD) to complex III and identified complex I as the site of elevated duanyu1670 production from NOD and B6 mitochondria. Using submitochondrial particles, we confirmed that in the context of the NOD or B6 nuclear genomes, mt-Nd2(c) elevates complex I-specific duanyu1670 production. In all assays mitochondria from mt-Nd2(a)-encoding strains exhibited low duanyu1670 production. Our data suggest that lowering overall mitochondrial duanyu1670 production is a key mechanism of disease protection provided by mt-Nd2(a).

KEYWORDS: {{ getKeywords(articleDetailText.words) }}