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

Caitlyn E. Bowman, Susana Rodriguez, Ebru S. Selen Alpergin, Michelle G. Acoba, Liang Zhao, Thomas Hartung, Steven M Claypool, Paul A Watkins, Michael J Wolfgang

Research output: Contribution to journalArticle

Abstract

Malonyl-coenzyme A (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, which 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. Malonate is an endogenous metabolite that inhibits mitochondrial metabolism. Using genetically modified human cells, Bowman et al. show that a mitochondrial malonyl-CoA synthetase, ACSF3, promotes malonate detoxification to enhance mitochondrial metabolic flux and is required for malonylation of mitochondrial proteins.

Original languageEnglish (US)
JournalCell Chemical Biology
DOIs
Publication statusAccepted/In press - Nov 10 2016

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Keywords

  • Acetyl-CoA
  • ACSF3
  • CRISPR/Cas
  • Malonate
  • Malonyl-CoA synthetase
  • Malonylation
  • Metabolomics
  • Mitochondrial metabolism
  • SIRT5
  • Succinylation

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Drug Discovery
  • Pharmacology

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