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Review
, 75, 122-30

Mitochondrial Quality Control in the Myocardium: Cooperation Between Protein Degradation and Mitophagy

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Review

Mitochondrial Quality Control in the Myocardium: Cooperation Between Protein Degradation and Mitophagy

Babette C Hammerling et al. J Mol Cell Cardiol.

Abstract

Mitochondria are critical for cardiomyocyte survival and maintenance of normal cardiac function. However, changes in the extra- or intracellular environments during stress can cause excessive damage to mitochondria and lead to activation of cell death. In fact, there is evidence that mitochondrial dysfunction is an important contributor to both development of heart failure and the aging process. To counteract the adverse effects resulting from mitochondrial damage, cells have evolved mitochondrial quality control pathways that act at both the protein and organelle levels. Quality control of proteins in the outer mitochondrial membrane is monitored by the ubiquitin-protease system, whereas chaperones and proteases act in the various compartments of the mitochondria. When the damage is too excessive and the degradation machinery is overwhelmed, the entire mitochondrion is eliminated by an autophagosome. Together, these pathways ensure that myocytes maintain a functional network of mitochondria which provides ATP for contraction. Unfortunately, chronic stress and aging can negatively affect proteins that are involved in the mitochondrial quality control pathways which leads to accumulation of dysfunctional mitochondria and loss of myocytes. In this review, we provide an overview of the proteins and pathways that regulate mitochondrial quality control in the cell with an emphasis on pathways involved in maintaining protein and organelle homeostasis. We also delve into the effects of reduced mitochondrial quality control on aging and cardiovascular disease.

Keywords: Aging; Autophagy; Mitochondria; Mitophagy; Parkin; Proteases.

Figures

Figure 1
Figure 1
Protein quality control in the mitochondrion. Outer mitochondrial membrane (OMM) E3 ubiquitin ligases such as March5 and MAPL tag proteins for degradation by the 26S proteasome, which is also responsible for the breakdown of the majority of ubiquitinated cytosolic proteins. Within the intermembrane space (IMS), HtrA2 is the chief protease in charge of protein degradation. Two ATPases Associated with diverse cellular Activity proteases, the matrix (m-) and the intermembrane (i-) AAA, identify misfolded polypeptides on their respective side of the IMM for degradation. Lon and ClpXP are the two most important QC proteases in the mitochondrial matrix. Lon is primarily responsible for the removal of oxidized proteins. ClpXP, composed of two ClpP subunits flanked by ClpX, plays a role in the unfolded protein response, degrading proteins unbound by chaperones (pink and green).
Figure 2
Figure 2
Mitochondrial Derived Vesicles. Small vesicles containing mitochondrial proteins and lipids bud off from mitochondria under baseline conditions and under oxidative stress. Formation of these vesicles requires the presence of PINK1 and Parkin. After budding off from the mitochondria, these vesicles fuse with lysosomes for degradation.
Figure 3
Figure 3
Mitochondrial Autophagy (mitophagy). (A) Upon loss of mitochondrial membrane potential, PINK1 accumulates on the OMM surface. PINK1 recruits Parkin, which ubiquitinates OMM proteins, thus inducing engulfment of the mitochondrion by the autophagosome through p62 and LC3. (B) Nix and BNIP3 function as autophagy receptors on mitochondria by binding to LC3 on the autophagosome. Both pathways result in the autophagic sequestration of the mitochondrion, fusion with a lysosome, and degradation of the organelle.

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