Abstract 279: Increased Drp1 Acetylation Mediates Lipid Overload-induced Cardiomyocyte Death & Heart Dysfunction

Abstract

Rationale: Lipid overload can cause diabetic cardiomyopathy (DCM), which is characterized by cardiomyocyte death, myocardial remodeling, and eventually contractile dysfunction. How excessive lipid supply impacts cardiac metabolism leading to DCM remains poorly understood. Objective: To investigate the role and mechanism of a mitochondrial fission protein, dynamin-related protein 1 (Drp1), in lipid overload-induced cardiomyocyte death and DCM. Methods and Results: Mice fed with high fat diet (HFD) for 18 weeks exhibited DCM phenotype including myocardial insulin resistance, fibrosis, hypertrophy, cardiomyocyte death and mild contractile dysfunction. Cultured adult cardiomyocytes incubated with high levels of palmitate also exhibited increased cell death and openings of the mitochondrial permeability transition pore. Mitochondrial fission was stimulated by HFD in the heart or by palmitate incubation in cultured adult cardiomyocytes. Mechanistically, lipid overload increased acetyl-CoA level and decreased NAD + level in the heart and in adult cardiomyocytes, leading to upregulation of Drp1 acetylation at lysine 642 (K642). Elevated Drp1 acetylation increased Drp1 protein level, its oligomerization and its phosphorylation at the activating serine 616 (S616) site. The excessively activated Drp1 translocated to mitochondria, induced fission, and bound with VDAC1 to promote cardiomyocyte death. Preventing Drp1 acetylation (K642R mutation), inhibiting Drp1 activity, or supplementing NAD + ameliorated palmitate-induced fission and cardiomyocyte death. In the hearts of HFD-fed monkeys, we observed increased Drp1 acetylation, oligomerization, and phosphorylation, which were accompanied with markers of DCM. Conclusions: These findings uncover a novel mechanism mediating lipid overload-induced heart hypertrophy and dysfunction. Excessive lipid supply created an intracellular environment that facilitated Drp1 acetylation, which increased its activity and mitochondrial translocation causing cardiomyocyte death. Thus, Drp1 could be a critical mediator for metabolic stress-induced heart dysfunction as well as a potential target for therapy.