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Review
. 2015 Mar;93(3):253-62.
doi: 10.1007/s00109-015-1254-6. Epub 2015 Jan 23.

Mitophagy and heart failure

Sarah E Shires  1 , Åsa B Gustafsson
Affiliations
Review

Mitophagy and heart failure

Sarah E Shires et al. J Mol Med (Berl). 2015 Mar.

Abstract

Cardiac mitochondria are responsible for generating energy in the form of ATP through oxidative phosphorylation and are crucial for cardiac function. Mitochondrial dysfunction is a major contributor to loss of myocytes and development of heart failure. Myocytes have quality control mechanisms in place to ensure a network of functional mitochondria. Damaged mitochondria are degraded by a process called mitochondrial autophagy, or mitophagy, where the organelle is engulfed by an autophagosome and subsequently delivered to a lysosome for degradation. Evidence suggests that mitophagy is important for cellular homeostasis, and reduced mitophagy leads to inadequate removal of dysfunctional mitochondria. In this review, we discuss the regulation of mitophagy and the emerging evidence of the cardioprotective role of mitophagy. We also address the prospect of therapeutically targeting mitophagy to treat patients with cardiovascular disease.

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Figures

Fig. 1
Fig. 1
Mechanisms of mitophagy. a Upon mitochondrial depolarization, PINK1 accumulates on the surface of the mitochondrion, recruiting Parkin to the outer mitochondrial membrane. Parkin polyubiquitinates mitochondrial membrane proteins, which allows them to be recognized by the adaptor protein p62. The autophagosome then engulfs the mitochondrion. b LC3 directly recognizes mitophagy receptor proteins BNIP3 and NIX resulting in mitochondrial clearance. c CK2 phosphorylates themitophagy receptor FUNDC1 to suppress its interaction with LC3. Hypoxia induces dephosphorylation of FUNDC1 by PGAM5, restoring its ability to interact with LC3 and trigger mitochondrial autophagy
Fig. 2
Fig. 2
Regulation of autophagy by intracellular calcium. a Mitochondrial uptake of calcium by the MCU results in increased ATP production, inhibition of AMPK, and suppression of autophagy. b Excessive levels of intracellular calcium leads to excessive mitochondrial calcium uptake, opening of the MPTP, and disruption of mitochondrial function. The reduced energy levels result in activation of AMPK and autophagy. Excess intracellular calcium also leads to direct activation of AMPK and autophagy via CaMKK-β
Fig. 3
Fig. 3
Mitophagy and mitochondrial quality control. a Normal mitophagy begins with the initiation and elongation of a double-membraned autophagic vesicle. The vesicle then sequesters and engulfs mitochondria for degradation. Proper regulation of mitophagy leads to mitochondrial quality control and cellular homeostasis. b Increased mitophagy may greatly reduce the pool of functional mitochondria. With too few mitochondria, the cell loses its ability to produce sufficient energy and eventually dies. c A reduction in mitophagy causes accumulation of dysfunctional mitochondria. The dysfunctional mitochondria generate excessive ROS and release pro-death proteins, triggering rapid cell death modification of Parkin and inhibition of mitophagy in the myocardium.
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