Acyl Coenzyme A Thioesterase Them5/Acot15 Is Involved in Cardiolipin Remodeling and Fatty Liver Development
- 1 July 2012
- journal article
- Published by Informa UK Limited in Molecular and Cellular Biology
- Vol. 32 (14), 2685-2697
- https://doi.org/10.1128/mcb.00312-12
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.Keywords
This publication has 37 references indexed in Scilit:
- Thioesterase superfamily member 2/acyl‐CoA thioesterase 13 (Them2/Acot13) regulates hepatic lipid and glucose metabolismThe FASEB Journal, 2012
- The complexity of cardiolipin in health and diseaseTrends in Biochemical Sciences, 2011
- Cardiac and Skeletal Muscle Defects in a Mouse Model of Human Barth SyndromeJournal of Biological Chemistry, 2011
- Functional and structural properties of mammalian acyl-coenzyme A thioesterasesProgress in Lipid Research, 2010
- Trichoplein/mitostatin regulates endoplasmic reticulum–mitochondria juxtapositionEMBO Reports, 2010
- Cardiolipin Remodeling by ALCAT1 Links Oxidative Stress and Mitochondrial Dysfunction to ObesityCell Metabolism, 2010
- OPA1 disease alleles causing dominant optic atrophy have defects in cardiolipin-stimulated GTP hydrolysis and membrane tubulationHuman Molecular Genetics, 2010
- Evolutionary divergence and functions of the human acyl-CoA thioesterase gene (ACOT) familyHuman Genomics, 2010
- Cardiolipin Molecular Species with Shorter Acyl Chains Accumulate in Saccharomyces cerevisiae Mutants Lacking the Acyl Coenzyme A-binding Protein Acb1pPublished by Elsevier BV ,2009
- The Mechanisms of Human Hotdog-fold Thioesterase 2 (hTHEM2) Substrate Recognition and Catalysis Illuminated by a Structure and Function Based Analysis,Biochemistry, 2009