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
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Amino Acid Sequence
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Animals
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Cardiolipins / metabolism*
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Crystallography, X-Ray
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Dimerization
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Fatty Liver / enzymology
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Fatty Liver / etiology*
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Fatty Liver / metabolism*
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HEK293 Cells
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Humans
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In Vitro Techniques
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Membrane Proteins / chemistry
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Knockout
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Mitochondria, Liver / metabolism
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Models, Biological
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Models, Molecular
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Molecular Sequence Data
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Palmitoyl-CoA Hydrolase / chemistry
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Palmitoyl-CoA Hydrolase / genetics
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Palmitoyl-CoA Hydrolase / metabolism*
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Protein Structure, Quaternary
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Thiolester Hydrolases / chemistry
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Thiolester Hydrolases / deficiency
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Thiolester Hydrolases / genetics
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Thiolester Hydrolases / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Cardiolipins
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Membrane Proteins
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Recombinant Proteins
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THEM4 protein, human
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Thiolester Hydrolases
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Palmitoyl-CoA Hydrolase
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Them5 protein, human