Mitophagy as a mitochondrial quality control mechanism in myocardial ischemic stress: from bench to bedside

Abstract

Myocardial ischemia reduces the supply of oxygen and nutrients to cardiomyocytes, leading to an energetic crisis or cell death. Mitochondrial dysfunction is a decisive contributor to the reception, transmission, and modification of cardiac ischemic signals. Cells with damaged mitochondria exhibit impaired mitochondrial metabolism and increased vulnerability to death stimuli due to disrupted mitochondrial respiration, reactive oxygen species overproduction, mitochondrial calcium overload, and mitochondrial genomic damage. Various intracellular and extracellular stress signaling pathways converge on mitochondria, so dysfunctional mitochondria tend to convert from energetic hubs to apoptotic centers. To interrupt the stress signal transduction resulting from lethal mitochondrial damage, cells can activate mitophagy (mitochondria-specific autophagy), which selectively eliminates dysfunctional mitochondria to preserve mitochondrial quality control. Different pharmacological and non-pharmacological strategies have been designed to augment the protective properties of mitophagy and have been validated in basic animal experiments and pre-clinical human trials. In this review, we describe the process of mitophagy in cardiomyocytes under ischemic stress, along with its regulatory mechanisms and downstream effects. Then, we discuss promising therapeutic approaches to preserve mitochondrial homeostasis and protect the myocardium against ischemic damage by inducing mitophagy.

Keywords: Bnip3; Fundc1; Mitochondria; Mitophagy; Myocardial ischemia; Parkin.

Fig. 1

Overview of the mitophagy machinery. Under ischemic/hypoxic conditions, fragmented mitochondria or mitochondria with structural damage caused by mitochondrial fission will experience a loss of mitochondrial membrane potential (ΔΨm). Mitochondria with a low ΔΨm recruit FUNDC1, which upon dephosphorylation at Ser 13 and Tyr18, binds to and recruits LC3 to the mitochondrial surface, leading to the formation of mitophagosomes. PINK1 is also translocated to mitochondria, where it induces Parkin to ubiquitinate proteins in the OMM. The ubiquitinated mitochondria interact with LC3 on lysosomes to form mitophagosomes. In addition, BNIP3 and NIX can directly bind LC3 via respective LIR motifs to mediate the formation of autophagic lysosomes independently of ubiquitination. Depending on the absence or presence of cellular stressors or organ injury, these processes will act to sustain mitochondrial self-renewal and homeostasis, necessary for normal cardiomyocyte activity, or may instead compromise cardiac performance by triggering mitophagy-related cardiomyocyte death