Mending a broken heart: the role of mitophagy in cardioprotection

Abstract

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.

Keywords: BNIP3; FUNDC1; autophagy; mitochondria; mitophagy; parkin.

Fig. 1.

Overview of mitochondrial autophagy. Mitochondrial autophagy begins with nucleation step by the BECLIN 1/VPS34/VPS15 complex, which initiates formation of the autophagosome. Next, ATG5/ATG12/ATG16 and light chain 3 (LC3) are involved in elongating the membrane. The autophagosome then fuses around a mitochondrion, sequestering it inside the mature double membrane vesicle. Finally, the autophagosome fuses with a lysosome and the mitochondrion is degraded by lysosomal hydrolases. ER, endoplasmic reticulum.

Fig. 2.

Mitophagy pathways. A: PINK1/Parkin-mediated mitophagy is initiated upon accumulation of PINK1 on the outer membrane of depolarized mitochondria. PINK1 then phosphorylates mitofusin 2 (MFN2), which leads to recruitment of Parkin. PINK1 also phosphorylates ubiquitin, and activated Parkin ubiquitinates its substrates. The p62 adaptor protein binds to ubiquitinated proteins and LC3 on the autophagosome. B: BNIP3 and NIX act as mitochondrial receptors and directly bind to LC3 to induce mitophagy. C: dephosphorylation of FUNDC1 by PGAM5 allows FUNDC1 to directly interact with LC3 to induce mitophagy.

Fig. 3.

Induction of autophagy by damaged mitochondria. A: BH3-only proteins directly induce autophagy by disrupting the BCL-2/BECLIN1 complex to release BECLIN1. The BECLIN1/VPS34/VPS15 complex can then induce autophagy. B: damaged mitochondria produce less ATP production, which activates the energy sensor AMPK. AMPK then activates Unc-51-like kinase (ULK)1, which activates the BECLIN1/VPS34/VPS15 complex. C: damaged mitochondria produce reactive oxygen species (ROS) that inhibit mammalian target of rapamycin (mTOR). Inhibition of mTOR leads to activation of autophagy. D: opening of the mitochondrial permeability transition pore (mPTP) results in influx of solutes and water into the mitochondrial matrix, which leads to disruption of the proton gradient and oxidative phosphorylation. It also causes depolarization and mitochondrial swelling that can activate autophagy.

Fig. 4.

Alternative pathways of mitochondrial clearance. A: ULK1 activates alternative autophagy via the BECLIN1/VPS34/VPS15 complex. The autophagosome membrane is derived from the trans-Golgi and is dependent on Rab9. The autophagosome sequesters the mitochondrion and fuses with a lysosome. B: microautophagy involves direct engulfment of cytosolic cargo into lysosomes. The lysosome forms an invagination to envelope the cargo. The internalized vesicle and its content are then degraded inside the lysosome by acid hydrolases.