Abstract 5379: Increased Myocardial Fatty Acid Uptake by Acyl-CoA Synthetase 1 Impairs Mitochondrial Function and Dynamics
Increased uptake and oxidation of fatty acids (FA) in diabetic hearts may contribute to mitochondrial dysfunction by promoting oxidative stress. To test this hypothesis, we investigated mice with cardiomyocyte-restricted overexpression of long-chain acyl-CoA synthetase 1 (MHC-ACS). In vivo PET studies revealed increased myocardial FA uptake (+120%; p<0.05) in MHC-ACS. Unexpectedly, FA oxidation and myocellular triglyceride content were unchanged, and PPARα-regulated FAO genes and PGC-1α-regulated OXPHOS genes were unaltered. However, cardiac content of the phospholipid precursors ceramide (+260%; p<0.05) and diacylglycerol (+40%; p<0.05) were increased. Mitochondrial cardiolipin content was decreased (−25%; p<0.05) and remodeled with substitution of 18:2 FA chains by unsaturated 22:6 FAs. Both ADP-stimulated mitochondrial O2 consumption (14.3±0.9 vs. 16.8±0.5 nmol/min/mgdw; p<0.05) and ATP synthesis (24.2±1.4 vs. 31.8±1.6 nmol/min/mgdw; p<0.05) were decreased in MHC-ACS in saponin-permeabilized cardiac fibers using palmitoyl-carnitine as a substrate. Mitochondrial superoxide production was increased by 75% (p<0.05). Electron microscopy in 3 to 24 week-old mice revealed increased mitochondrial number, which was highest at 3 weeks (3wk +210%, 12wk +120%, 24wk +130%; all p<0.05), and reduced mitochondrial size. Translocation of the mitochondrial fission protein dynamin-related protein 1 (Drp1) from cytosol to mitochondria was absent (p<0.05) in MHC-ACS, but not in controls. Mitochondrial membrane content of the fission protein fission 1 and the fusion proteins mitofusin 1 and 2 were unchanged. These morphological changes are consistent with increased mitochondrial fission and reduced Drp1 likely represents an adaptive response. Thus remodeling of the myocardial lipid pool and mitochondrial membrane lipid composition are associated with impaired mitochondrial dynamics and represents a novel mechanism for lipid-induced mitochondrial dysfunction in the heart.