Abstract
In heart failure patients, the accumulation of damaged mitochondria is frequently observed in cardiomyocytes. Damaged mitochondria are degraded through mitophagy, a form of mitochondria-specific autophagy. Previously, we identified BCL2L13 as a mitophagy receptor and demonstrated its ability to induce mitophagy and mitochondrial fission in mammalian cells and the necessity of phosphorylation at Ser272 for its activation. However, the in vivo role of BCL2L13 remains unclear. In this study, we investigated the cardiac function of BCL2L13 using bcl2l13 knockout mice and knock-in mice expressing a non-phosphorylatable BCL2L13(S272A) mutant. In the hearts of these genetically modified mice, pressure overload leads to suppressed mitochondrial fission and mitophagy, resulting in reduced ATP production. Additionally, we analyzed bcl2l13 and prkn/parkin double-knockout mice but found no additive effects of prkn deletion. Furthermore, we identified PRKAA2/AMPKα2 as the kinase responsible for phosphorylating BCL2L13 at Ser272. These findings highlight the critical role of BCL2L13 and its phosphorylation in activating mitophagy as part of the cardiac stress response and suggest that targeting BCL2L13 phosphorylation could serve as a potential therapeutic strategy for heart failure.Abbreviation: BCL2L13, BCL2 like 13; ATG, autophagy related; MAP1LC3B/LC3B, microtubule-associated protein 1 light chain 3 beta; KO, knockout; TAC, transverse aortic constriction; LVFS, left ventricular fractional shortening; ROS, reactive oxygen species; DKO, double knockout; siRNA, small interfering RNA; PRKAA2/AMPKα2, protein kinase, AMP-activated alpha 2 catalytic subunit; CCCP, carbonyl cyanide 3-chlorophenylhydrazone.