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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.
SUPPLEMENTAL MATERIAL
Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00312-12.
ACKNOWLEDGMENTS
We thank Michael Rebhan for help with the initial bioinformatics analysis, Ahmad Bechara for discussion of the EM data, David Knight for MS analysis, and Gregor Lotz for respirometry analysis. We also thank Susanne Schenk for Them5 antibodies generation and the staff of beamlines X10SA and X06DA at the Swiss Light Source (Villigen, Switzerland) for their excellent support in X-ray data collection.
E.Z. was supported by a Swiss Bridge fellowship. Work in Manchester was undertaken with the FLS Biomolecular Analysis Facility. The Friedrich Miescher Institute for Biomedical Research is part of the Novartis Research Foundation.