Mitophagy in cardiovascular diseases: molecular mechanisms, pathogenesis, and treatment

Abstract

With the growing prevalence of cardiovascular disease (CVD), there is an urgent need to explore non-conventional therapeutic measures to alleviate the burden of CVD on global healthcare. Mitochondrial injury plays a cardinal role in the pathogenesis of CVD. Mitochondrial dynamics and mitophagy are essential machineries that govern mitochondrial health in cardiomyocytes in physiological and pathophysiological settings. However, with the onset and progression of CVD, homeostasis of mitophagy is disturbed through largely unknown pathological mechanisms, causing mitochondrial damage and ultimately cardiomyocyte death. In this review we decipher the dual regulatory role of mitophagy in CVD pathogenesis, summarize controversies in mitophagy, and highlight recently identified compounds capable of modulating mitophagy. We share our perspectives on future mitophagy research directions in the context of CVD.

Keywords: cardiovascular disease; heart failure; mitophagy; mitophagy inducers; myocardial infarction; therapeutics.

Fig. 1.. PINK1-PRKN-dependent Mitophagy

Mitochondrial damage/depolarization instigates PINK1 recruitment and stabilization on the OMM. Subsequently, PINK1 phosphorylates and recruits PRKN to the OMM. PRKN mediates ubiquitination and polyubiquitination of OMM proteins, leading to a bridge formation between targeted mitochondria and the autophagosome. ULK1 and BECN1 also participate in further recruitment of PRKN, a step that is referred to as amplification of PINK1/PRKN mitophagy. Ultimately, damaged/depolarized mitochondria engulfment within the autophagosome will end up with lysosomal fusion and degradation, leaving the cardiomyocytes free of damaged mitochondria. Initial signaling for mitophagy activation also includes AMP-, ROS-, and Ca²⁺-mediated activation of AMPK, which turns on transcription factors and autophagy regulators. The transcription factors relocate to the nucleus and transactivate mitophagy/autophagy genes that participate in the formation of autophagosomes. However, autophagy regulators inhibit MTORC1, resulting in the activation of the autophagy initiation complex (ULK1 complex), thus, forming phagophore (the initial membrane that ultimately matures into autophagosome). Of note, mitochondria damage is the initial inducer of AMPK activation as it causes cytosolic accumulation of Ca²⁺, ROS, and AMP.