Reactive oxygen species (ROS) 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 ROS-associated conditions. Our previous studies have demonstrated that the adenine containing allele (mt-Nd2a) is also strongly associated with resistance against type 1 diabetes in mice. In this report we have confirmed that the cytosine-containing allele (mt-Nd2c) results in elevated mitochondrial ROS production. Using inhibitors of the electron transport chain, we show that when in combination with nuclear genes from the alloxan-resistant (ALR) strain, mt-Nd2c increases ROS from complex III. Furthermore, by using alamethicin-permeabilized mitochondria, we measured a significant increase in electron transport chain-dependent ROS production from all mt-Nd2c-encoding strains including ALR.mtNOD, non-obese diabetic (NOD), and C57BL/6 (B6). Studies employing alamethicin and inhibitors were able to again localize the heightened ROS production in ALR.mt NOD to complex III and identified complex I as the site of elevated ROS production from NOD and B6 mitochondria. Using submitochondrial particles, we confirmed that in the context of the NODor B6 nuclear genomes, mt-Nd2 c elevates complex I-specific ROS production. In all assays mitochondria from mt-Nd2a-encoding strains exhibited low ROS production. Our data suggest that lowering overall mitochondrial ROS production is a key mechanism of disease protection provided by mt-Nd2a. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.
CITATION STYLE
Gusdon, A. M., Votyakova, T. V., & Mathews, C. E. (2008). mt-Nd2a suppresses reactive oxygen species production by mitochondrial complexes I and III. Journal of Biological Chemistry, 283(16), 10690–10697. https://doi.org/10.1074/jbc.M708801200
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