Interdependence of Parkin-Mediated Mitophagy and Mitochondrial Fission in Adult Mouse Hearts
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 cardiomyocyte-specific interruption of 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 very low levels in normal mouse hearts, but were upregulated after cardiomyocyte-directed Drp1 gene deletion in adult mice. Alone, forced cardiomyocyte Parkin overexpression activated mitophagy without adverse effects. Likewise, cardiomyocyte-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 cardiomyocyte 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/SQSTM1 and processed LC3. Consequently, mitochondrial content of Drp1-deficient hearts was preserved. Parkin deletion did not alter characteristic mitochondrial enlargement of Drp1-deficient cardiomyocytes.
Conclusions: Parkin is rare in normal hearts and dispensable for constitutive mitophagic quality control. Ablating Drp1 in adult mouse cardiomyocytes not only interrupts mitochondrial fission, but markedly upregulates Parkin, thus provoking mitophagic mitochondrial depletion that contributes to the lethal cardiomyopathy.
- Received May 14, 2015.
- Revision received May 28, 2015.
- Accepted June 2, 2015.