title: Loss of long-chain acyl-CoA synthetase isoform 1 impairs cardiac autophagy and mitochondrial structure through mechanistic target of rapamycin complex 1 activation.
abstract: Because hearts with a temporally induced knockout of acyl-CoA synthetase 1 (Acsl1(T-/-)) are virtually unable to oxidize fatty acids, glucose use increases 8-fold to compensate. This metabolic switch activates mechanistic target of rapamycin complex 1 (mTORC1), which initiates growth by increasing protein and RNA synthesis and fatty acid metabolism, while decreasing autophagy. Compared with controls, Acsl1(T-/-) hearts contained 3 times more mitochondria with abnormal structure and displayed a 35-43% lower respiratory function. To study the effects of mTORC1 activation on mitochondrial structure and function, mTORC1 was inhibited by treating Acsl1(T-/-) and littermate control mice with rapamycin or vehicle alone for 2 wk. Rapamycin treatment normalized mitochondrial structure, number, and the maximal respiration rate in Acsl1(T-/-) hearts, but did not improve ADP-stimulated oxygen consumption, which was likely caused by the 33-51% lower ATP synthase activity present in both vehicle- and rapamycin-treated Acsl1(T-/-) hearts. The turnover of microtubule associated protein light chain 3b in Acsl1(T-/-) hearts was 88% lower than controls, indicating a diminished rate of autophagy. Rapamycin treatment increased autophagy to a rate that was 3.1-fold higher than in controls, allowing the formation of autophagolysosomes and the clearance of damaged mitochondria. Thus, long-chain acyl-CoA synthetase isoform 1 (ACSL1) deficiency in the heart activated mTORC1, thereby inhibiting autophagy and increasing the number of damaged mitochondria.
authors.affiliation: Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Trisha J
authors.initials: TJ
authors.lastname: Grevengoed
authors.affiliation: Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Cooper
authors.affiliation: Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Young
authors.affiliation: Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Ellis
authors.affiliation: Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA rcoleman@unc.edu.
authors.forename: Rosalind A
authors.initials: RA
authors.lastname: Coleman
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D003066:Coenzyme A Ligases / Q000172:deficiency*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010101:Oxygen Consumption / Q000187:drug effects / Q000235:genetics; D006180:Proton-Translocating ATPases / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D006180:Proton-Translocating ATPases; C544400:ACSL1 protein, mouse; D003066:Coenzyme A Ligases; D020123:Sirolimus
keywords: ATP synthase; glucose metabolism; heart metabolism; lipid metabolism; β-oxidation