Endogenous Drp1 Mediates Mitochondrial Autophagy and Protects the Heart Against Energy Stress
Rationale: Both fusion and fission contribute to mitochondrial quality control. How unopposed fusion affects survival of cardiomyocytes (CMs) and left ventricular (LV) function in the heart is poorly understood.
Objective: We investigated the role of Dynamin-related protein 1 (Drp1), a GTPase that mediates mitochondrial fission, in mediating mitochondrial autophagy, ventricular function, and stress resistance in the heart.
Methods and Results: Drp1 downregulation induced mitochondrial elongation, accumulation of damaged mitochondria, and increased apoptosis in CMs at baseline. Drp1 downregulation also suppressed autophagosome formation and autophagic flux at baseline and in response to glucose deprivation in CMs. The lack of lysosomal translocation of mitochondrially-targeted Keima indicates that Drp1 downregulation suppressed mitochondrial autophagy. Mitochondrial elongation and accumulation of damaged mitochondria were also observed in tamoxifen-inducible cardiac-specific Drp1 knockout (Drp1-CKO) mice. Following Drp1 downregulation, Drp1-CKO mice developed LV dysfunction, preceded by mitochondrial dysfunction, and died within 13 weeks. Autophagic flux is significantly suppressed in Drp1-CKO mice. Although LV function in cardiac-specific Drp1 heterozygous KO (Drp1-hetCKO) mice was normal at 12 weeks of age, LV function decreased more severely after 48 hours of fasting and the infarct size/area at risk after ischemia/reperfusion (I/R) was significantly greater in Drp1-hetCKO than in control mice.
Conclusions: Disruption of Drp1 induces mitochondrial elongation, inhibits mitochondrial autophagy, and causes mitochondrial dysfunction, thereby promoting cardiac dysfunction and increased susceptibility to I/R.
- Received January 19, 2014.
- Revision received October 13, 2014.
- Accepted October 17, 2014.