title: Acyl coenzyme A thioesterase Them5/Acot15 is involved in cardiolipin remodeling and fatty liver development.
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.
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. elena.zhuravleva@fmi.ch
authors.forename: Elena
authors.initials: E
authors.lastname: Zhuravleva
authors.forename: Heinz
authors.initials: H
authors.lastname: Gut
authors.forename: Debby
authors.initials: D
authors.lastname: Hynx
authors.forename: David
authors.initials: D
authors.lastname: Marcellin
authors.forename: Christopher K E
authors.initials: CK
authors.lastname: Bleck
authors.forename: Christel
authors.initials: C
authors.lastname: Genoud
authors.forename: Peter
authors.initials: P
authors.lastname: Cron
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Keusch
authors.forename: Bettina
authors.initials: B
authors.lastname: Dummler
authors.forename: Mauro Degli
authors.initials: MD
authors.lastname: Esposti
authors.forename: Brian A
authors.initials: BA
authors.lastname: Hemmings
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002308:Cardiolipins / Q000378:metabolism*; D018360:Crystallography, X-Ray; D019281:Dimerization; D005234:Fatty Liver / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000378:metabolism; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010170:Palmitoyl-CoA Hydrolase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020836:Protein Structure, Quaternary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013869:Thiolester Hydrolases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002308:Cardiolipins; D008565:Membrane Proteins; D011994:Recombinant Proteins; C437985:THEM4 protein, human; D013869:Thiolester Hydrolases; D010170:Palmitoyl-CoA Hydrolase; C574999:Them5 protein, human