AMPKα2 Protects Against the Development of Heart Failure by Enhancing Mitophagy via PINK1 Phosphorylation
Rationale: Mitochondrial dysfunction plays an important role in heart failure (HF). However, the molecular mechanisms regulating mitochondrial functions via selective mitochondrial autophagy (mitophagy) are poorly understood.
Objective: We sought to determine the role of AMP-activated protein kinase (AMPK) in selective mitophagy during HF.
Methods and Results: An isoform shift from AMPKα2 to AMPKα1 was observed in failing-heart samples from HF patients and transverse aortic constriction (TAC)-induced mice, accompanied by decreased mitophagy and mitochondrial function. The recombinant adeno-associated virus Serotype 9-mediated overexpression of AMPKα2 in mouse hearts prevented the development of TAC-induced chronic HF by increasing mitophagy and improving mitochondrial function. In contrast, AMPKα2−/− mutant mice exhibited an exacerbation of the early progression of TAC-induced HF via decreases in cardiac mitophagy. In isolated adult mouse cardiomyocytes (CMs), AMPKα2 overexpression mechanistically rescued the impairment of mitophagy after phenylephedrine (PE) stimulation for 24 h. Genetic knockdown of AMPKα2, but not AMPKα1, by short interfering RNA suppressed the early phase (6 h) of PE-induced compensatory increases in mitophagy. Furthermore, AMPKα2 specifically interacted with phosphorylated PTEN-induced putative kinase 1 (PINK1) at Ser495 after PE stimulation. Subsequently, phosphorylated PINK1 recruited the E3 ubiquitin ligase, Parkin, to depolarized mitochondria, and then enhanced the role of the PINK1-Parkin-sequestosome-1 pathway involved in cardiac mitophagy. This increase in cardiac mitophagy was accompanied by the elimination of damaged mitochondria, improvement in mitochondrial function, decrease in reactive oxygen species (ROS) production, and apoptosis of CMs. Finally, Ala mutation of PINK1 at Ser495 partially suppressed AMPKα2 overexpression-induced mitophagy and improvement of mitochondrial function in PE-stimulated CMs, whereas Asp (phosphorylation-mimic) mutation promoted mitophagy after PE stimulation.
Conclusions:In failing hearts, the dominant AMPKα isoform switched from AMPKα2 to AMPKα1, which accelerated HF. The results show that phosphorylation of Ser495 in PINK1 by AMPKα2 was essential for efficient mitophagy to prevent the progression of HF.
- Received October 31, 2017.
- Revision received December 20, 2017.
- Accepted December 27, 2017.