Abstract 17574: Drp1-dependent Mitochondrial Autophagy Plays A Protective Role In Response To Pressure Overload Induced Mitochondrial Dysfunction And Heart Failure
Dynamin-related protein 1 (Drp1) plays an essential role in maintaining mitochondrial (Mt) quality control through Mt fission and mitophagy. We investigated how Mt function, mitophagy and Drp1 are regulated in the heart during pressure overload (PO) and their roles in regulating cardiac function. Mice were subjected to transverse aortic constriction (TAC) for 1, 3, 5, 7, 14 and 30 days. Left ventricular (LV) weight/tibial length (LVW/TL) was significantly elevated at Day 5 (TAC vs sham; 6.21 ± 0.10 vs 4.59 ± 0.10, p<0.05). Ejection fraction (EF) was maintained at Day 7 (82.1±3.4 vs 78.4±3.2%), but gradually decreased thereafter (at Day 30, 51.0±4.5, p<0.05). Both Mt ATP content (-65.0%, p<0.05) and production (-32.0%, p<0.05) were reduced significantly at Day 7 and thereafter. Mt mass, evaluated by electron microscopy (EM), was reduced (-30.0%, p<0.05) transiently at Day 5. Drp1 was phosphorylated at S616 and accumulated in mitochondria, peaking at Day 3. In EM analyses, autophagosomes containing mitochondria were observed at Day 5 and 7, but not at other time points. Mt DNA content was also transiently decreased below control levels at Day 3 and 5. The levels of COX I and COX IV, Mt matrix proteins, were decreased significantly at Day 3, 5 and 7 compared to sham. These results suggest that PO induces Drp1 translocation and Mt autophagy only transiently around Day 3-7, and that mitochondrial dysfunction develops thereafter. PO-induced decreases in EF (58.2± 6.2 vs 82.2 ± 1.0%, p<0.05), and increases in LVW/TL (6.43 ± 0.82 vs 5.16 ± 0.47, p<0.05) and lung weight/TL (13.31 ± 0.63 vs 7.01 ± 0.66, p<0.05) were all exacerbated in cardiac-specific heterozygous Drp1 knock out (Drp-hetCKO) mice compared to in control mice. Mt mass was significantly greater (1.21 ± 0.46 vs 1.00 ± 0.02, p<0.05) and Mt ATP production was significantly lower (0.58 ± 0.05 vs 1.00 ± 0.02, p<0.05) in Drp-hetCKO than in control mice, indicating accumulation of dysfunctional mitochondria in Drp-hetCKO mice. Although PO transiently induces Mt translocation of Drp1 and Mt autophagy, Mt dysfunction eventually develops, followed by development of heart failure. Endogenous Drp1 protects the heart from failure during PO by inducing degradation of damaged mitochondria.
Author Disclosures: A. Shirakabe: None. Y. Ikeda: None. P. Zai: None. T. Saito: None. J. Sadoshima: None.
- © 2015 by American Heart Association, Inc.