372 - Neuronal Deletion of Manganese Superoxide Dismutase Altered TCA Cycle Metabolism and Caused Severe Peripheral Nerve Demyelination in Mice

Abstract

Oxidative stress and mitochondrial dysfunction have been increasingly recognized as contributing factors for the pathogenesis of various diseases, including neurodegenerative diseases. Manganese superoxide dismutase (MnSOD) is the sole mitochondrial matrix enzyme that converts dismutate superoxide to hydrogen peroxide. Previous studies investigating the role of MnSOD in the central nervous system have used mice lacking this enzyme in neuronal stem cells and showed perinatal lethality and severe growth retardation. However, the underlying mechanisms for the phenotype of brain-specific MnSOD knockout (BSOD) mice is not well understood. Here used BSOD mice on a C57B background and show that mitochondrial function was preserved in whole brain sections despite increased superoxide levels. We also demonstrated that BSOD mice fail to feed at about post-natal day 15 and develop severe diabetic ketoacidosis. Although the overall morphology of the central nervous system was not altered in BSOD mice, peripheral nerves ultrastructure was severely affected as evidenced by myelin delamination. Interestingly, metabolomic analysis of the sciatic nerves of BSOD mice showed reduced polyol pathway and increased glycerol levels. Furthermore, there was a massive accumulation of the oncometabolite 2-hydroxyglutarate both in whole brain homogenates and in sciatic nerves of BSOD mice. Taken together, these results indicate that MnSOD deletion in neuronal cells causes peripheral neuropathy in part via impairment of mitochondrial metabolism.