RATIONALE: Both fusion and fission contribute to mitochondrial quality control. 
How unopposed fusion affects survival of cardiomyocytes and left ventricular 
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 cardiomyocytes 
at baseline. Drp1 downregulation also suppressed autophagosome formation and 
autophagic flux at baseline and in response to glucose deprivation in 
cardiomyocytes. 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 mice. After Drp1 
downregulation, cardiac-specific Drp1 knockout mice developed left ventricular 
dysfunction, preceded by mitochondrial dysfunction, and died within 13 weeks. 
Autophagic flux is significantly suppressed in cardiac-specific Drp1 knockout 
mice. Although left ventricular function in cardiac-specific Drp1 heterozygous 
knockout mice was normal at 12 weeks of age, left ventricular function decreased 
more severely after 48 hours of fasting, and the infarct size/area at risk after 
ischemia/reperfusion was significantly greater in cardiac-specific Drp1 
heterozygous knockout 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 ischemia/reperfusion.