Mending a broken heart: the role of mitophagy in cardioprotection

Abstract

Moyzis AG, Sadoshima J, Gustafsson ÅB. Mending a broken heart: the role of mitophagy in cardioprotection. Am J Physiol Heart Circ Physiol 308: H183-H192, 2015. First published November 25, 2014 doi:10.1152/ajpheart.00708.2014.-The heart is highly energy dependent with most of its energy provided by mitochondrial oxidative phosphorylation. Mitochondria also play a role in many other essential cellular processes including metabolite synthesis and calcium storage. Therefore, maintaining a functional population of mitochondria is critical for cardiac function. Efficient degradation and replacement of dysfunctional mitochondria ensures cell survival, particularly in terminally differentiated cells such as cardiac myocytes. Mitochondria are eliminated via mitochondrial autophagy or mitophagy. In the heart, mitophagy is an essential housekeeping process and required for cardiac homeostasis. Reduced autophagy and accumulation of impaired mitochondria have been linked to progression of heart failure and aging. In this review, we discuss the pathways that regulate mitophagy in cells and highlight the cardioprotective role of mitophagy in response to stress and aging. We also discuss the therapeutic potential of targeting mitophagy and directions for future investigation.autophagy; mitophagy; mitochondria; parkin; BNIP3; FUNDC1 THE HEART IS HIGHLY ENERGY dependent, and the majority of its energy is provided by mitochondrial oxidative phosphorylation. Mitochondria also play a role in many other cellular processes including metabolite synthesis and calcium storage (41). Hence, maintaining a functional population of mitochondria is critical for cardiac function. Damaged mitochondria produce less ATP, generate greater amounts of reactive oxygen species (ROS), and can activate apoptosis and/or necrosis. Thus efficient removal of dysfunctional mitochondria and biogenesis of functional mitochondria are critical for the maintenance of cellular homeostasis. This is of particular importance in cells such as cardiac myocytes, which are terminally differentiated. The mechanism that the cell uses to eliminate damaged mitochondria is known as mitochondrial autophagy or mitophagy, and involves selective sequestering of the organelle inside an autophagosome and subsequent fusion with a lysosome where degradation occurs (98). Autophagy was initially considered to be a nonselective bulk degradation pathway, especially during stress such as starvation. However, given the critical role of mitochondria in myocytes, it seems unlikely that degradation of mitochondria is a random process, especially during energy deficient conditions such as starvation. This could lead to the degradation of too many mitochondria and compromise cellular survival. A recent study examined changes in the cellular proteome during starvation and found that cytosolic proteins, multiprotein complexes, and organelles show distinct patterns of degradation (46). This study reported that cytosolic proteins are degraded early during starvation, whereas mitochondria are degra...

Proteotoxicity and Cardiac Dysfunction

“…When damaged, mitochondria can become tagged for degradation through a variety of pathways. 175,176 The best understood signaling cascade for mitophagy involves PINK1/Parkin, wherein PINK1, a serine/threonine kinase, phosphorylates proteins on the mitochondrial outer membrane and recruits parkin, an E3 ubiquitin ligase, to ubiquitinate these proteins through K63 linkages, which are thought to signal lysosomal rather than proteasomal degradation. 176 Adaptor proteins such as p62 bind and signal autophagosome recruitment and engulfment of the mitochondrion by binding to LC3.…”

“…175,176 The best understood signaling cascade for mitophagy involves PINK1/Parkin, wherein PINK1, a serine/threonine kinase, phosphorylates proteins on the mitochondrial outer membrane and recruits parkin, an E3 ubiquitin ligase, to ubiquitinate these proteins through K63 linkages, which are thought to signal lysosomal rather than proteasomal degradation. 176 Adaptor proteins such as p62 bind and signal autophagosome recruitment and engulfment of the mitochondrion by binding to LC3. 176 Upon ischemic insult or IPC, parkin translocates to mitochondria, which in turn signals the autophagic adaptor p62 to the mitochondria, suggesting that ischemic insult is inducing mitophagy.…”

“…176 Adaptor proteins such as p62 bind and signal autophagosome recruitment and engulfment of the mitochondrion by binding to LC3. 176 Upon ischemic insult or IPC, parkin translocates to mitochondria, which in turn signals the autophagic adaptor p62 to the mitochondria, suggesting that ischemic insult is inducing mitophagy. 177 That similar signaling cascades are activated in both ischemic injury and IPC imply this pathway is cardioprotective.…”

Mitophagy imbalance in cardiomyocyte ischaemia/reperfusion injury

“…4 Adequate mitophagy is necessary for the maintenance of cardiomyocyte survival. 5,6 However, I/R can induce insufficient or excessive mitophagy, thus inevitably leading to cardiomyocyte injury. This review summarizes the recent advances in our understanding of mitophagy imbalance in cardiomyocyte injury upon I/R and its molecular mechanism underlying mitophagy abnormalities.…”

Gerontoxanthone I and Macluraxanthone Induce Mitophagy and Attenuate Ischemia/Reperfusion Injury

“…IR injury can lead to mitochondria damaged, which further harm to cardiomyocytes. Therefore, it is necessary to remove damaged mitochondria via mitophagy for the maintenance of cardiomyocyte survival (Kubli and Gustafsson, 2012;Moyzis et al, 2015;Li et al, 2019). Our precious results illustrated that GeX1 H9c2 cells.…”