Abstract 91: Interdependence of Mitochondrial Fission and Mitophagy in Adult Mouse Hearts

Abstract

The role of Drp1-mediated mitochondrial fission in normal hearts is controversial. Cardiomyocyte mitochondria are hypo-dynamic, but mitochondrial dynamism factors are abundantly expressed. Cardiac-specific Drp1 gene deletion (KO) provokes mitochondrial enlargement, MPTP-dependent cardiomyocyte loss, and dilated cardiomyopathy (Song et al Cell Metab, 2015). We postulated that Drp1-dependent mitochondrial fission is essential for triage and elimination of damaged cardiomyocyte mitochondria by Parkin-mediated mitophagy. Others described no benefit of Parkin KO in mice with perinatal cardiac Drp1 KO (Kageyama et al EMBO J, 2014), but these Parkin KO mice have little basal phenotype due to germ-line compensation. Here, we assessed the individual and interactive roles of Parkin and Drp1 in adult mouse hearts by conditionally ablating each gene (Cre-Lox at 8 wks), separately and in combination. Parkin KO hearts appeared normal; as reported, Drp1 KO caused lethal cardiomyopathy after 6-7 wks. Cardiac-specific Parkin KO concomitant with Drp1 KO ameliorated the underlying cardiomyopathy by: 1. Increasing survival (94% vs 56%; P<0.0001); 2. Enhancing cardiac contractility (LV FS 36.2±4.0 vs 23.2±1.7%; P=0.01); 3. Decreasing adverse remodeling (LV r/h 5.0±0.5 vs 6.3±0.4; P=0.05); 4. Reducing cardiomyocyte necrosis (1.9±0.5 vs 5.0±1.2%; P=0.05) and replacement fibrosis (33.3±5.3 vs 13.0±1.5%; P=0.02); 5. Attenuating mitochondrial deficiency (5.7±0.4 vs 4.7±0.6 μg/mg; P=0.20). Deleting Parkin did not affect mitochondrial enlargement or respiratory function in Drp1 KO cardiomyocytes, but normalized mitochondrial-associated LC3 and p62, mitophagy markers increased in cardiac Drp1 KO. These studies show how Drp1-mediated mitochondrial fission and Parkin-mediated mitophagy interact to maintain the quality of cardiac mitochondria: Interrupting mitochondrial fission (Drp1 KO) prevents segregation of damaged mitochondrial components into daughter organelles normally targeted for mitophagy; mitophagy thus ultimately consumes fission-defective parent organelles. Parkin KO suppresses generalized mitophagy, postponing (but not preventing) the Drp1 KO cardiomyopathy.