Role of the malonyl-CoA synthetase ACSF3 in mitochondrial metabolism

Adv Biol Regul. 2019 Jan;71:34-40. doi: 10.1016/j.jbior.2018.09.002. Epub 2018 Sep 5.


Malonyl-CoA is a central metabolite in fatty acid biochemistry. It is the rate-determining intermediate in fatty acid synthesis but is also an allosteric inhibitor of the rate-setting step in mitochondrial long-chain fatty acid oxidation. While these canonical cytoplasmic roles of malonyl-CoA have been well described, malonyl-CoA can also be generated within the mitochondrial matrix by an alternative pathway: the ATP-dependent ligation of malonate to Coenzyme A by the malonyl-CoA synthetase ACSF3. Malonate, a competitive inhibitor of succinate dehydrogenase of the TCA cycle, is a potent inhibitor of mitochondrial respiration. A major role for ACSF3 is to provide a metabolic pathway for the clearance of malonate by the generation of malonyl-CoA, which can then be decarboxylated to acetyl-CoA by malonyl-CoA decarboxylase. Additionally, ACSF3-derived malonyl-CoA can be used to malonylate lysine residues on proteins within the matrix of mitochondria, possibly adding another regulatory layer to post-translational control of mitochondrial metabolism. The discovery of ACSF3-mediated generation of malonyl-CoA defines a new mitochondrial metabolic pathway and raises new questions about how the metabolic fates of this multifunctional metabolite intersect with mitochondrial metabolism.

Keywords: Antimetabolite; Fatty acid; Malonate; Malonic acid; Malonyl-CoA; Mitochondria; Succinate dehydrogenase; Synthetase.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Citric Acid Cycle / physiology*
  • Coenzyme A Ligases / genetics
  • Coenzyme A Ligases / metabolism*
  • Humans
  • Malonates / metabolism
  • Malonyl Coenzyme A / genetics
  • Malonyl Coenzyme A / metabolism*
  • Mitochondria / enzymology*
  • Mitochondria / genetics


  • Malonates
  • Malonyl Coenzyme A
  • malonic acid
  • ACSF3 protein, human
  • Coenzyme A Ligases