RATIONALE: The role of Parkin in hearts is unclear. Germ-line Parkin knockout 
mice have normal hearts, but Parkin is protective in cardiac ischemia. 
Parkin-mediated mitophagy is reportedly either irrelevant, or a major factor, in 
the lethal cardiomyopathy evoked by cardiac myocyte-specific interruption of 
dynamin-related protein 1 (Drp1)-mediated mitochondrial fission.
OBJECTIVE: To understand the role of Parkin-mediated mitophagy in normal and 
mitochondrial fission-defective adult mouse hearts.
METHODS AND RESULTS: Parkin mRNA and protein were present at low levels in 
normal mouse hearts, but were upregulated after cardiac myocyte-directed Drp1 
gene deletion in adult mice. Alone, forced cardiac myocyte Parkin overexpression 
activated mitophagy without adverse effects. Likewise, cardiac myocyte-specific 
Parkin deletion evoked no adult cardiac phenotype, revealing no essential 
function for, and tolerance of, Parkin-mediated mitophagy in normal hearts. 
Concomitant conditional Parkin deletion with Drp1 ablation in adult mouse hearts 
prevented Parkin upregulation in mitochondria of fission-defective hearts, also 
increasing 6-week survival, improving ventricular ejection performance, 
mitigating adverse cardiac remodeling, and decreasing cardiac myocyte necrosis 
and replacement fibrosis. Underlying the Parkin knockout rescue was suppression 
of Drp1-induced hyper-mitophagy, assessed as ubiquitination of mitochondrial 
proteins and mitochondrial association of autophagosomal p62/sequestosome 1 
(SQSTM1) and processed microtubule-associated protein 1 light chain 3 (LC3-II). 
Consequently, mitochondrial content of Drp1-deficient hearts was preserved. 
Parkin deletion did not alter characteristic mitochondrial enlargement of 
Drp1-deficient cardiac myocytes.
CONCLUSIONS: Parkin is rare in normal hearts and dispensable for constitutive 
mitophagic quality control. Ablating Drp1 in adult mouse cardiac myocytes not 
only interrupts mitochondrial fission, but also markedly upregulates Parkin, 
thus provoking mitophagic mitochondrial depletion that contributes to the lethal 
cardiomyopathy.