Abstract
Mitophagy, which mediates the selective elimination of dysfunctional mitochondria, is essential for cardiac homeostasis. Mitophagy is regulated mainly by PTEN-induced putative kinase protein-1 (PINK1)/parkin pathway but also by FUN14 domain-containing 1 (FUNDC1) or Bcl2 interacting protein 3 (BNIP3) and BNIP3-like (BNIP3L/NIX) pathways. Several studies have shown that dysregulated mitophagy is involved in cardiac dysfunction induced by aging, aortic stenosis, myocardial infarction or diabetes. The cardioprotective role of mitophagy is well described, whereas excessive mitophagy could contribute to cell death and cardiac dysfunction. In this review, we summarize the mechanisms involved in the regulation of cardiac mitophagy and its role in physiological condition. We focused on cardiac mitophagy during and following myocardial infarction by highlighting the role and the regulation of PI NK1/parkin-; FUNDC1-; BNIP3- and BNIP3L/NIX-induced mitophagy during ischemia and reperfusion.
Highlights
Despite the best current therapy, ischemic cardiac diseases remain a major public health concern as the leading causes of morbidity and mortality in the world [1]
We summarize the mechanisms involved in the regulation of cardiac mitophagy and its role in physiological condition
Cardiac I/R injury induced by 30 min of ischemia followed by 2 h of reperfusion induces excessive PINK1/parkin-mediated mitophagy in heart [98], in cardiomyoblasts H9c2 [98] and in microvascular endothelial cells leading to apoptosis or necrosis [7]
Summary
Despite the best current therapy, ischemic cardiac diseases remain a major public health concern as the leading causes of morbidity and mortality in the world [1]. A process called cardiac ischemia/reperfusion (I/R) injury leads to a loss of microvessel integrity, endothelial cells activation, inflammation, ROS production, mitochondrial damages and apoptosis [6,7]. AMP activated protein kinase (AMPK), an important metabolic sensor in the heart, is activated by decreased cellular ATP levels and initiates autophasome formation by mammalian target of rapamycin (mTOR) inhibition [18] and activates mitophagy by phosphorylation of PINK1 at Ser-495 [39]. Others proteins have been described to interact with LC3, thanks to LIR sequence such as Bcl interacting protein 3 (BNIP3) [42] and BNIP3-like (BNIP3L/NIX) [43–45] If both are well known to have pro-apoptotic function [46,47], it was shown that BNIP3 induces mitophagy in adult cardiomyocytes [42] and that dynamin-related protein 1 (Drp1), a regulator of mitochondrial fission, is required for this process [48,49]. ULK1 phosphorylates Beclin-1 at Ser-14 [53] and Ser-30 [54] leading to its activation as well as FUNDC1 at serine 17, which enhances its binding to LC3 [55]
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