Abstract 14493: Cardiac Specific Disruption of Drp-1 Causes the Development of Cardiac Dysfunction via Inhibition of Autophagy and Induction of Apoptosis
Mitochondrial health is maintained by mitochondrial fission and fusion. Fission affects mitochondrial function and turnover either directly or indirectly through mitophagy. Although mitochondrial fission can be detrimental during ischemia/reperfusion, its role in regulating cardiac function and autophagy in the heart under baseline conditions remains to be elucidated. Dynamin-related protein 1 (Drp-1) is a GTPase that plays an essential role in mediating mitochondrial fission. We generated cardiac specific conditional Drp-1 KO mice, in which expression of Drp-1 is downregulated in a tamoxifen-dependent manner. We used DRP1 fl/fl, αMHC-MerCreMer, and wild type (WT) mice as controls. The mice were subjected to tamoxifen injection (20mg / ip) for 5 days. All analyses were conducted 5 weeks after the last injection. Cardiac expression of Drp-1 was 50% lower in Drp-1 KO than in control mice. COX-IV was higher in Drp-1 KO than in control mice, suggesting that the mitochondrial content was higher in Drp-1 KO than in control mice. Cardiac systolic function at 5 months of age was lower in Drp-1 KO than in control mice (Ejection Fraction; Drp-1 KO: 46 ±4, P<0.01, DRP1 fl/fl: 66±5, αMHC-MerCreMer: 61±3, WT: 66±2%). Both left ventricular weight/tibial length (4.48±0.38, P<0.05, 4.09±0.50, 3.64±0.57, 4.12±0.53mg/mm) and cardiomyocyte cross-sectional area were greater in Drp-1 KO than in control mice (559±71, P<0.01, 264±11, 293±2, 293±14 μm²). The amount of LC-3 II was significantly smaller (0.49±0.17, P<0.05, 1.04±0.45, 1.24±0.30, 1.66±0.33) whereas that of p62 was higher(1.11±0.15, P<0.01, 0.15±0.04, 0.27±0.16, 0.15±0.04) in Drp-1 KO than in control mice. The amount of cleaved caspase3 (0.64±0.28, P<0.05, 0.10±0.05, 0.11±0.05, 0.16±0.04) and the number of TUNEL positive cells (0.20 ±0.10, P<0.01, 0.03±0.06, 0.07±0.06, 0.03±0.06%) were higher in Drp-1 KO than in control mice. These results suggest that Drp-1 KO inhibits autophagy and induces apoptosis, thereby causing attenuation of mitochondrial turnover and development of cardiac dysfunction. Mitochondrial fission mediated by Drp-1 plays an essential role in maintaining the level of autophagy and mitochondrial turnover, thereby maintaining cardiac function in the heart at baseline.
- © 2012 by American Heart Association, Inc.