Abstract 11959: A Reduced Mitochondrial Environment Impairs FA Metabolism and Mitochondrial Function by Modulating Sirt3-Mediated Deacetylation of Mitochondrial Proteins
Overexpression of manganese superoxide dismutase (Sod2) in cardiomyocytes has been reported to preserve cardiac function under conditions of myocardial oxidative stress, such as diabetes. However, the impact of increased scavenging of ROS on mitochondrial (mito) function and substrate utilization in non-stressed hearts is incompletely understood. We therefore examined transgenic mice with cardiomyocyte-restricted overexpression of Sod2 (MHC-Sod2) to test the hypothesis that increased antioxidant delivery to the mitochondria could alter redox balance and modulate NAD+- and redox-dependent pathways. In MHC-Sod2 mouse hearts, oxidative modifications of mito proteins were reduced by 30-80% and the NAD+/NADH ratio was reduced by 71% relative to controls (WT) (p<0.05). Activities of mito deacetylases were reduced by 10%, p<0.05, which correlated with a 2.3 fold increase in total lysine acetylation of mito proteins (p<0.001). In addition, mito content of the NAD+-dependent deacetylase SIRT3 was reduced (-32%, p<0.01) versus WT, as was electron transport chain (ETC) complex I (CI) subunit NDUFA9 (-37%, p<0.001). In blue native gels, overall content of ETC complexes were also reduced by 40% for CI, and 20 to 30% for CIII-CV, p<0.01. Activities of CI and CII were reduced by 60% and 20%, respectively, p<0.0001. Consistent with these data, mito respiration and ATP production in response to palmitoyl carnitine, and palmitate oxidation rates in isolated perfused working hearts were decreased in MHC-Sod2 hearts by 31% and 27% (p<0.05) respectively relative to WT. As a consequence of decreased fatty acid (FA) utilization, levels of potentially toxic lipid intermediates such as ceramide and diacylglycerol were elevated by 91% and 60%, respectively, p<0.05. To exclude non-specific toxic effects of transgene overexpression, we observed that oxidative stress and mito dysfunction, following pressure overload was ameliorated in MHC-Sod2 hearts following aortic banding. Thus increased ROS scavenging impairs mito function and FA oxidative capacity in non-stressed hearts by mechanisms that may involve changes in NAD+-dependent deacetylation of mito proteins, despite being cardioprotective under conditions of increased oxidative stress.
- © 2011 by American Heart Association, Inc.