title: Human trifunctional protein alpha links cardiolipin remodeling to beta-oxidation.
abstract: Cardiolipin (CL) is a mitochondrial membrane phospholipid which plays a key role in apoptosis and supports mitochondrial respiratory chain complexes involved in the generation of ATP. In order to facilitate its role CL must be remodeled with appropriate fatty acids. We previously identified a human monolysocardiolipin acyltransferase activity which remodels CL via acylation of monolysocardiolipin (MLCL) to CL and was identical to the alpha subunit of trifunctional protein (αTFP) lacking the first 227 amino acids. Full length αTFP is an enzyme that plays a prominent role in mitochondrial β-oxidation, and in this study we assessed the role, if any, which this metabolic enzyme plays in the remodeling of CL. Purified human recombinant αTFP exhibited acyl-CoA acyltransferase activity in the acylation of MLCL to CL with linoleoyl-CoA, oleoyl-CoA and palmitoyl-CoA as substrates. Expression of αTFP increased radioactive linoleate or oleate or palmitate incorporation into CL in HeLa cells. Expression of αTFP in Barth Syndrome lymphoblasts, which exhibit reduced tetralinoleoyl-CL, elevated linoleoyl-CoA acylation of MLCL to CL in vitro, increased mitochondrial respiratory Complex proteins and increased linoleate-containing species of CL. Knock down of αTFP in Barth Syndrome lymphoblasts resulted in greater accumulation of MLCL than those with normal αTFP levels. The results clearly indicate that the human αTFP exhibits MLCL acyltransferase activity for the resynthesis of CL from MLCL and directly links an enzyme of mitochondrial β-oxidation to CL remodeling.
authors.affiliation: Department of Pharmacology and Therapeutics, Center for Research and Treatment of Atherosclerosis, Manitoba Institute of Child Health, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: William A
authors.initials: WA
authors.lastname: Taylor
authors.forename: Edgard M
authors.initials: EM
authors.lastname: Mejia
authors.forename: Ryan W
authors.initials: RW
authors.lastname: Mitchell
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Choy
authors.forename: Genevieve C
authors.initials: GC
authors.lastname: Sparagna
authors.forename: Grant M
authors.initials: GM
authors.lastname: Hatch
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D000217:Acyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002308:Cardiolipins / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation; D005227:Fatty Acids / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D063991:Mitochondrial Trifunctional Protein; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D010171:Palmitoyl Coenzyme A / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D013379:Substrate Specificity; D013974:Thyroxine / Q000494:pharmacology
chemical_list: D000214:Acyl Coenzyme A; D002308:Cardiolipins; D005227:Fatty Acids; D008246:Lysophospholipids; D009097:Multienzyme Complexes; D011993:Recombinant Fusion Proteins; C017585:oleoyl-coenzyme A; D010171:Palmitoyl Coenzyme A; C026562:linoleoyl-coenzyme A; D000217:Acyltransferases; C401969:monolysocardiolipin acyltransferase; D063991:Mitochondrial Trifunctional Protein; D013974:Thyroxine