Abstract 15630: Mitochondrial Reactive Oxygen Species (mitoROS) in Lipotoxic Hearts Induces Post-Translational Modifications of Drp1 that Promotes Mitochondrial Fission
Lipotoxicity, which is characterized by increased accumulation in cardiomyocytes of toxic lipid intermediates, contributes to cardiac dysfunction in obesity and diabetes. The present study was designed to elucidate the mechanisms by which cardiac lipid overload alters mitochondrial dynamics and mitochondrial energetics. We first examined an animal model of moderate lipid overload in the heart, i.e. mice with low-level overexpression (3-fold) of long chain acyl-CoA synthetase 1 (ACS1) driven by the cardiomyocyte-specific α-MHC promoter (ACStg mice). In these mice, palmitate bio-distribution, measured by in vivo PET, was increased by 2-fold. This 2-fold increase in palmitate uptake induced a striking fragmentation of the mitochondrial network, characterized by numerous small mitochondria and mitochondrial proliferation in cardiomyocytes, that was associated with decreased palmitoyl-carnitine oxidation in permeabilized fibers and increased mitoROS generation. Phosphorylation of Dynamin-related protein 1 (Drp1) at Ser637 was increased by 1.7 fold in ACStg hearts. To determine if increased mitoROS was responsible for changes in mitochondrial dynamics, we examined mice with overexpression of mitochondrial superoxide dismutase (Sod2) driven by α-MHC promoter (Sod2tg mice). Surprisingly, Sod2 overexpression in cardiomyocytes increased mitochondrial fusion and decreased mitoROS generation. Mitochondrial fragmentation in ACStg mice was partially rescued by Sod2 overexpression. In addition, mitoROS overproduction and the associated Drp1 post-translational modifications were reversed. To establish an in vitro model we incubated neonatal rat ventricular cardiomyocytes (NRVMs) with 500μM palmitate and observed mitochondrial fragmentation that was blocked by co-incubation with 10μM Mdivi1 (Drp1 inhibitor) or 400μM MnTBAP (non-selective ROS scavenger). Taken together, these experiments strongly suggest that enhanced mitoROS induces post-translational modification of Drp1 that regulates mitochondrial dynamics, revealing a novel mechanism for mitochondrial and cardiac dysfunction in lipotoxic cardiomyopathy.
- © 2013 by American Heart Association, Inc.