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Review
. 2012 Oct 12;111(9):1208-21.
doi: 10.1161/CIRCRESAHA.112.265819.

Mitochondria and mitophagy: the yin and yang of cell death control

Dieter A Kubli  1 , Åsa B Gustafsson
Affiliations
Review

Mitochondria and mitophagy: the yin and yang of cell death control

Dieter A Kubli et al. Circ Res. .

Abstract

Mitochondria are primarily responsible for providing the contracting cardiac myocyte with a continuous supply of ATP. However, mitochondria can rapidly change into death-promoting organelles. In response to changes in the intracellular environment, mitochondria become producers of excessive reactive oxygen species and release prodeath proteins, resulting in disrupted ATP synthesis and activation of cell death pathways. Interestingly, cells have developed a defense mechanism against aberrant mitochondria that can cause harm to the cell. This mechanism involves selective sequestration and subsequent degradation of the dysfunctional mitochondrion before it causes activation of cell death. Induction of mitochondrial autophagy, or mitophagy, results in selective clearance of damaged mitochondria in cells. In response to stress such as ischemia/reperfusion, prosurvival and prodeath pathways are concomitantly activated in cardiac myocytes. Thus, there is a delicate balance between life and death in the myocytes during stress, and the final outcome depends on the complex cross-talk between these pathways. Mitophagy functions as an early cardioprotective response, favoring adaptation to stress by removing damaged mitochondria. In contrast, increased oxidative stress and apoptotic proteases can inactivate mitophagy, allowing for the execution of cell death. Herein, we discuss the importance of mitochondria and mitophagy in cardiovascular health and disease and provide a review of our current understanding of how these processes are regulated.

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Figures

Figure 1
Figure 1
Induction of autophagy. BCL-2/BCL-XL prevents induction of autophagy by binding BECLIN1 and AMBRA1. Displacement by BH3-only proteins leads to activation of the BECLIN1-VPS34-VPS15 complex and phagophore nucleation. Elongation of the membrane requires two ubiquitin-like conjugation systems: ATG12-ATG5-ATG16L, and conjugation of LC3-I with phosphatidylethanolamine (PE) to form LC3-II. After maturation of the autophagosome, it fuses with the lysosome to degrade the cargo. (Illustration Credit: Ben Smith).
Figure 2
Figure 2
Mechanisms of mitochondrial membrane permeabilization. A. Anti-apoptotic BCL-2 family proteins, such as BCL-2 and BCL-XL, inhibit BAX/BAK-mediated outer mitochondrial membrane permeabilization. BAX/BAK activation causes release of cytotoxic proteins, slow loss of DYm, and culminates in apoptosis. B. Opening of the mPTP results in rapid influx of solutes and water which causes dissipation of the Dym, inner membrane swelling and subsequent outer membrane rupture. Destruction of the outer membrane releases cytotoxic proteins into the cytosol and leads to necrotic cell death. Anti-apoptotic BCL-2 proteins also prevent mPTP opening, while pro-apoptotic proteins such as Bax can enhance mPTP opening.
Figure 3
Figure 3
Regulation of mitophagy. Damaged mitochondria undergo DRP1-mediated fission prior to mitophagy. Reduced mitochondrial membrane potential leads to accumulation of PINK1 and subsequent recruitment of the E3 ubiquitin ligase Parkin to mitochondria. Parkin promotes ubiquitination of proteins in the mitochondrial membrane, which _targets the damaged mitochondrion for removal by an autophagosome. The healthy mitochondrial fragment will undergo fusion mediated by MFN1/2 and OPA1. (Illustration Credit: Ben Smith).
Figure 4
Figure 4
Removal of mitochondria via autophagy adaptors or autophagy receptors. A. The p62 protein interacts with ubiquitinated proteins on the mitochondrion. The complex is then selectively sequestered by an autophagosome through the interaction between p62 and LC3. B. Autophagy receptors on the mitochondria such as Bnip3 and Nix interact directly with LC3 on the autophagosome. (Illustration Credit: Ben Smith).
Figure 5
Figure 5
Balance between life and death during stress. A. Mild stress causes damage to a few mitochondria, which are rapidly sequestered by autophagosomes. B. In response to severe stress, there is overwhelming mitochondrial damage that autophagosomes are unable to efficiently clear. These mitochondria will release pro-death proteins from the intermembrane space (IMS), such as cytochrome c, AIF, and SMAC/Diablo, that will activate cell death pathways.
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