Acyl coenzyme A thioesterase Them5/Acot15 is involved in cardiolipin remodeling and fatty liver development

Mol Cell Biol. 2012 Jul;32(14):2685-97. doi: 10.1128/MCB.00312-12. Epub 2012 May 14.

Abstract

Acyl coenzyme A (acyl-CoA) thioesterases hydrolyze thioester bonds in acyl-CoA metabolites. The majority of mammalian thioesterases are α/β-hydrolases and have been studied extensively. A second class of Hotdog-fold enzymes has been less well described. Here, we present a structural and functional analysis of a new mammalian mitochondrial thioesterase, Them5. Them5 and its paralog, Them4, adopt the classical Hotdog-fold structure and form homodimers in crystals. In vitro, Them5 shows strong thioesterase activity with long-chain acyl-CoAs. Loss of Them5 specifically alters the remodeling process of the mitochondrial phospholipid cardiolipin. Them5(-/-) mice show deregulation of lipid metabolism and the development of fatty liver, exacerbated by a high-fat diet. Consequently, mitochondrial morphology is affected, and functions such as respiration and β-oxidation are impaired. The novel mitochondrial acyl-CoA thioesterase Them5 has a critical and specific role in the cardiolipin remodeling process, connecting it to the development of fatty liver and related conditions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Amino Acid Sequence
  • Animals
  • Cardiolipins / metabolism*
  • Crystallography, X-Ray
  • Dimerization
  • Fatty Liver / enzymology
  • Fatty Liver / etiology*
  • Fatty Liver / metabolism*
  • HEK293 Cells
  • Humans
  • In Vitro Techniques
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Mitochondria, Liver / metabolism
  • Models, Biological
  • Models, Molecular
  • Molecular Sequence Data
  • Palmitoyl-CoA Hydrolase / chemistry
  • Palmitoyl-CoA Hydrolase / genetics
  • Palmitoyl-CoA Hydrolase / metabolism*
  • Protein Structure, Quaternary
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Thiolester Hydrolases / chemistry
  • Thiolester Hydrolases / deficiency
  • Thiolester Hydrolases / genetics
  • Thiolester Hydrolases / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Cardiolipins
  • Membrane Proteins
  • Recombinant Proteins
  • THEM4 protein, human
  • Thiolester Hydrolases
  • Palmitoyl-CoA Hydrolase
  • Them5 protein, human

Associated data

  • PDB/4AE7
  • PDB/4AE8