TY - JOUR
T1 - Loss of long-chain acyl-CoA synthetase isoform 1 impairs cardiac autophagy and mitochondrial structure through mechanistic target of rapamycin complex 1 activation
AU - Grevengoed, Trisha Jean
AU - Cooper, Daniel E
AU - Young, Pamela A
AU - Ellis, Jessica M
AU - Coleman, Rosalind A
N1 - © FASEB.
PY - 2015/11/1
Y1 - 2015/11/1
N2 - Because hearts with a temporally induced knockout of acyl-CoA synthetase 1 (Acsl1T2/2) 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, Acsl1T2/2 hearts contained 3 times more mitochondriawith 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 Acsl1T2/2 and littermate control mice with rapamycin or vehicle alone for 2 wk. Rapamycin treatment normalized mitochondrial structure, number, and the maximal respiration rate in Acsl1T2/2 hearts, but did not improve ADP-stimulated oxygen consumption, whichwas likely caused by the 33-51%lowerATP synthase activity present in both vehicle- and rapamycintreated Acsl1T2/2 hearts. The turnover of microtubule associated protein light chain 3b in Acsl1T2/2 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.-Grevengoed, T. J., Cooper,D. E., Young, P. A., Ellis, J. M.,Coleman,R. A. Loss of long-chain acyl-CoA synthetase isoform 1 impairs cardiac autophagy and mitochondrial structure through mechanistic target of rapamycin complex 1 activation.
AB - Because hearts with a temporally induced knockout of acyl-CoA synthetase 1 (Acsl1T2/2) 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, Acsl1T2/2 hearts contained 3 times more mitochondriawith 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 Acsl1T2/2 and littermate control mice with rapamycin or vehicle alone for 2 wk. Rapamycin treatment normalized mitochondrial structure, number, and the maximal respiration rate in Acsl1T2/2 hearts, but did not improve ADP-stimulated oxygen consumption, whichwas likely caused by the 33-51%lowerATP synthase activity present in both vehicle- and rapamycintreated Acsl1T2/2 hearts. The turnover of microtubule associated protein light chain 3b in Acsl1T2/2 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.-Grevengoed, T. J., Cooper,D. E., Young, P. A., Ellis, J. M.,Coleman,R. A. Loss of long-chain acyl-CoA synthetase isoform 1 impairs cardiac autophagy and mitochondrial structure through mechanistic target of rapamycin complex 1 activation.
U2 - 10.1096/fj.15-272732
DO - 10.1096/fj.15-272732
M3 - Journal article
C2 - 26220174
SN - 0892-6638
VL - 29
SP - 4641
EP - 4653
JO - FASEB journal : official publication of the Federation of American Societies for Experimental Biology
JF - FASEB journal : official publication of the Federation of American Societies for Experimental Biology
IS - 11
ER -