Sirtuin 5 Reduces Malonylation in Non-mitochondrial Metabolic Pathways in Diabetic Kidney Disease

Early diabetic kidney disease (DKD) is marked by dramatic metabolic reprogramming due to nutrient excess, mitochondrial dysfunction, and increased renal energy requirements from hyperfiltration. We hypothesized that changes in metabolism in DKD may be regulated by Sirtuin 5 (SIRT5), a deacylase that removes post-translational modifications derived from acyl-coenzyme A and has been demonstrated to regulate numerous metabolic pathways. We found decreased malonylation in kidney cortex (~80% proximal tubules) of type 2 diabetic BKS db/db mice, associated with increased SIRT5 expression. Proteomics analysis of malonylated peptides found that proteins with significantly decreased malonylated lysines in the db/db cortex were enriched in non-mitochondrial metabolic pathways: glycolysis and peroxisomal fatty acid oxidation (FAO). To confirm relevance of these findings in human disease, we analyzed diabetic kidney transcriptomic data from a cohort of Southwestern American Indians which revealed tubulointerstitial specific increase in Sirt5 expression. Overexpression of SIRT5 in cultured human proximal tubules demonstrated increased aerobic glycolysis with reduced mitochondrial metabolism, and conversely with decreased SIRT5 expression, there was reduced glycolysis and increased mitochondrial metabolism. These findings suggest that SIRT5 may lead to differential nutrient partitioning and utilization in DKD. Our findings highlight a previously unrecognized role for SIRT5 in metabolic reprogramming in DKD.