The Mammalian Malonyl-CoA Synthetase ACSF3 Is Required for Mitochondrial Protein Malonylation and Metabolic Efficiency

Abstract

Summary Malonyl-CoA is a central metabolite in mammalian fatty acid biochemistry generated and utilized in the cytoplasm; however, little is known about noncanonical organelle-specific malonyl-CoA metabolism. Intramitochondrial malonyl-CoA is generated by a malonyl-CoA synthetase, ACSF3, that produces malonyl-CoA from malonate, an endogenous competitive inhibitor of succinate dehydrogenase. To determine the metabolic requirement for mitochondrial malonyl-CoA, ACSF3 knockout (KO) cells were generated by CRISPR/Cas-mediated genome editing. ACSF3 KO cells exhibited elevated malonate and impaired mitochondrial metabolism. Unbiased and targeted metabolomics analysis of KO and control cells in the presence or absence of exogenous malonate revealed metabolic changes dependent on either malonate or malonyl-CoA. While ACSF3 was required for the metabolism and therefore detoxification of malonate, ACSF3-derived malonyl-CoA was specifically required for lysine malonylation of mitochondrial proteins. Together, these data describe an essential role for ACSF3 in dictating the metabolic fate of mitochondrial malonate and malonyl-CoA in mammalian metabolism.

SIRT5 deacylates metabolism-related proteins and attenuates hepatic steatosis in ob/ob mice

“…Interestingly, proteomic hypermalonylation in ob/ob mice has been observed by our group and confirmed by Bowman et al [ 23 , 24 ]. Consistent with this observation, malonyl-CoA, the group donor of malonylation, has been shown to elevate in the skeletal muscle and the liver of OLETF rats and in muscle biopsies of patients with obesity and T2D [ 25 , 26 ].…”

“…Malonyl-CoA was first recognized as the intermediate of the fatty acid synthesis pathway and is produced mainly in cytosol by the enzymes acetyl-CoA carboxylases 1 and 2 (ACC1/2). A recent study discovered that malonyl-CoA can also be synthesized directly from malonate by ACSF3 in the mitochondria of mammalian cells [ 24 ]. The wide distribution of malonyl-CoA in both the cytosol and mitochondria might explain the malonylated protein localization.…”

Interferon Gamma Reprograms Host Mitochondrial Metabolism through Inhibition of Complex II To Control Intracellular Bacterial Replication

“…Differences in responses to 4OI or DMM between species may be indicative of variations in hydrolysis rates of these compounds by esterases to their active metabolites and/or variation in complex II regulatory networks. Furthermore, in addition to direct inhibition of complex II, DMM can influence malonate-related fatty acid (FA) synthesis/oxidation (49), which may be more integral to mouse macrophage function. Further studies characterizing mouse and human primary macrophage regulatory elements of complex II and dependence on specific metabolic networks will be informative in selecting treatments that appropriately modulate mitochondrial function to control infection.…”

Loss of Hepatic Mitochondrial Long-Chain Fatty Acid Oxidation Confers Resistance to Diet-Induced Obesity and Glucose Intolerance

“…Serum insulin (Crystal Chem), Fgf21, Gdf15, Igfbp1 and Adiponectin (R&D Systems) were measured by ELISA. Total saponified fatty acids were quantified by GCMS as we have previously described (Bowman et al, 2017; Reamy and Wolfgang, 2011). Acylcarnitines were quantified as previously described (Lee et al, 2016b).…”