mt-Nd2a suppresses reactive oxygen species production by mitochondrial complexes I and III.
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-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 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-Nd2(c) 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-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 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 NOD or B6 nuclear genomes, mt-Nd2(c) elevates complex I-specific ROS production. In all assays mitochondria from mt-Nd2(a)-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-Nd2(a).
Gusdon
Aaron M
AM
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida 32610-0275, USA.
Votyakova
Tatyana V
TV
Mathews
Clayton E
CE
D000408:Alamethicin / Q000494:pharmacology; D000483:Alleles; D000818:Animals; D004579:Electron Transport; D042967:Electron Transport Complex I / Q000378:metabolism*; D014450:Electron Transport Complex III / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D009245:NADH Dehydrogenase / Q000378:metabolism / Q000502:physiology*; D010641:Phenotype; D017382:Reactive Oxygen Species
D017382:Reactive Oxygen Species; D000408:Alamethicin; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I; C502385:mt-Nd2 protein, mouse; D014450:Electron Transport Complex III