Excess in mitochondrial reactive oxygen species (ROS) is considered as a major cause of cellular oxidative stress. NADPH, the main intracellular reductant, has a key role in keeping glutathione in its reduced form GSH, which scavenges ROS and thus protects the cell from oxidative damage. Here, we report that SIRT5 desuccinylates and deglutarylates isocitrate dehydrogenase 2 (IDH2) and glucose-6-phosphate dehydrogenase (G6PD), respectively, and thus activates both NADPH-producing enzymes. Moreover, we show that knockdown or knockout of SIRT5 leads to high levels of cellular ROS. SIRT5 inactivation leads to the inhibition of IDH2 and G6PD, thereby decreasing NADPH production, lowering GSH, impairing the ability to scavenge ROS, and increasing cellular susceptibility to oxidative stress. Our study uncovers a SIRT5-dependent mechanism that regulates cellular NADPH homeostasis and redox potential by promoting IDH2 desuccinylation and G6PD deglutarylation.
L-2-Hydroxyglutarate aciduria (L-2-HGA) is an autosomal recessive neurometabolic disorder caused by a mutation in the L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene. In this study, we generated L2hgdh knockout (KO) mice and observed a robust increase of L-2-hydroxyglutarate (L-2-HG) levels in multiple tissues. The highest levels of L-2-HG were observed in the brain and testis, with a corresponding increase in histone methylation in these tissues. L2hgdh KO mice exhibit white matter abnormalities, extensive gliosis, microglia-mediated neuroinflammation, and an expansion of oligodendrocyte progenitor cells (OPCs). Moreover, L2hgdh deficiency leads to impaired adult hippocampal neurogenesis and late-onset neurodegeneration in mouse brains. Our data provide in vivo evidence that L2hgdh mutation leads to L-2-HG accumulation, leukoencephalopathy, and neurodegeneration in mice, thereby offering new insights into the pathophysiology of L-2-HGA in humans.KEYWORDS L2HGDH, 2-HG, leukoencephalopathy, gliosis, neurodegeneration T he rare, autosomal recessive neurometabolic disorders D-2-hydroxyglutaric aciduria (D-2-HGA) and L-2-hydroxyglutaric aciduria (L-2-HGA) are characterized by the accumulation of D-2-hydroxyglutarate (D-2-HG) and L-2-hydroxyglutarate (L-2-HG), respectively, in body fluids. Genetic characterization has shown that 50% of the D-2-HGA population and the majority of L-2-HGA patients harbor pathogenic mutations in D2HGDH and L2HGDH genes, respectively (1-3). The other half of D-2-HGA patients have a gain-of-function mutation in isocitrate dehydrogenase 2 (IDH2) at the residue of R140 (R140Q), which leads to abnormally high accumulation of D-2-HG (4). Based on phenotypic severity in patients, D-2-HGA is classified as mild type I (D2HGDH mutation) and severe type II (IDH2 mutation) (4, 5). Of note, 2-HG concentrations are 2-to 8-fold higher for type II D-2-HGA than type I D-2-HGA patients (4, 6, 7), suggesting that
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