title: Acyl-CoA synthetase 1 deficiency alters cardiolipin species and impairs mitochondrial function.
abstract: Long-chain acyl-CoA synthetase 1 (ACSL1) contributes more than 90% of total cardiac ACSL activity, but its role in phospholipid synthesis has not been determined. Mice with an inducible knockout of ACSL1 (Acsl1(T-/-)) have impaired cardiac fatty acid oxidation and rely on glucose for ATP production. Because ACSL1 exhibited a strong substrate preference for linoleate, we investigated the composition of heart phospholipids. Acsl1(T-/-) hearts contained 83% less tetralinoleoyl-cardiolipin (CL), the major form present in control hearts. A stable knockdown of ACSL1 in H9c2 rat cardiomyocytes resulted in low incorporation of linoleate into CL and in diminished incorporation of palmitate and oleate into other phospholipids. Overexpression of ACSL1 in H9c2 and HEK-293 cells increased incorporation of linoleate into CL and other phospholipids. To determine whether increasing the content of linoleate in CL would improve mitochondrial respiratory function in Acsl1(T-/-) hearts, control and Acsl1(T-/-) mice were fed a high-linoleate diet; this diet normalized the amount of tetralinoleoyl-CL but did not improve respiratory function. Thus, ACSL1 is required for the normal composition of several phospholipid species in heart. Although ACSL1 determines the acyl-chain composition of heart CL, a high tetralinoleoyl-CL content may not be required for normal function.
authors.affiliation: Department of Nutrition, University of North Carolina at Chapel Hill, NC 27599.
authors.forename: Trisha J
authors.initials: TJ
authors.lastname: Grevengoed
authors.affiliation: Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Martin
authors.affiliation: Department of Pharmacology and Toxicology, East Carolina University, Greenville, NC 27858.
authors.forename: Lalage
authors.initials: L
authors.lastname: Katunga
authors.affiliation: Department of Nutrition, University of North Carolina at Chapel Hill, NC 27599.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Cooper
authors.affiliation: Department of Pharmacology and Toxicology, East Carolina University, Greenville, NC 27858.
authors.forename: Ethan J
authors.initials: EJ
authors.lastname: Anderson
authors.affiliation: Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Murphy
authors.affiliation: Department of Nutrition, University of North Carolina at Chapel Hill, NC 27599.
authors.forename: Rosalind A
authors.initials: RA
authors.lastname: Coleman
mesh_terms: D000818:Animals; D002308:Cardiolipins / Q000378:metabolism*; D002460:Cell Line; D019069:Cell Respiration; D003066:Coenzyme A Ligases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D004041:Dietary Fats / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D019787:Linoleic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D021381:Protein Transport; D051381:Rats
chemical_list: D002308:Cardiolipins; D004041:Dietary Fats; D005227:Fatty Acids; C523441:tetralinoleoylcardiolipin; D019787:Linoleic Acid; C544400:ACSL1 protein, mouse; D003066:Coenzyme A Ligases; C561832:Acsl1 protein, rat
keywords: cardiomyocyte dysfunction; fatty acid/oxidation; heart fatty acid/metabolism; phospholipids/biosynthesis; phospholipids/metabolism