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Mitophagy as a Protective Mechanism against Myocardial Stress

Jihoon Nah, Shigeki Miyamoto, Junichi Sadoshima

10.1002/cphy.c170005

Source: Volume 7, Issue 4, October 2017

Published online: September 2017

Full Article on Wiley Online Library



ABSTRACT

Mitochondria are dynamic organelles that can undergo fusion, fission, biogenesis, and autophagic elimination to maintain mitochondrial quality control. Since the heart is in constant need of high amounts of energy, mitochondria, as a central energy supply source, play a crucial role in maintaining optimal cardiac performance. Therefore, it is reasonable to assume that mitochondrial dysfunction is associated with the pathophysiology of heart diseases. In non‐dividing, post‐mitotic cells such as cardiomyocytes, elimination of dysfunctional organelles is essential to maintaining cellular function because non‐dividing cells cannot dilute dysfunctional organelles through cell division. In this review, we discuss the recent findings regarding the physiological role of mitophagy in the heart and cardiomyocytes. Moreover, we discuss the functional role of mitophagy in the progression of cardiovascular diseases, including myocardial ischemic injury, diabetic cardiomyopathy, cardiac hypertrophy, and heart failure. © 2017 American Physiological Society. Compr Physiol 7:1407‐1424, 2017.

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Figure 1. Figure 1. Mitochondrial quality control systems. During mitochondrial fusion, both Mfn1 and Mfn2 mediate OMM fusion while OPA1 simultaneously mediates IMM fusion. Membrane bounded L‐OPA1 can be cleaved to S‐OPA1 by YME1L and OMA1. The balance of between L‐OPA1 and S‐OPA1 affects mitochondrial fission and fusion. Mitochondrial fission is promoted by translocation of Drp1 to mitochondria. Translocation of Drp1 is mediated by Drp1 adaptors including MFF, MiD49, and Mid51. In addition, post‐translational modification of Drp1 regulates translocation of Drp1. Phosphorylation of Drp1 at Ser616 by Cdk1/cyclin B enhances Drp1 localization on the OMM. In contrast, phosphorylation of Drp1 at Ser637 by PKA facilitates Drp1 dissociation from the OMM. Mitochondrial Drp1 mediates fission by generating mechanical force. Depolarized mitochondria are selectively eliminated by mitophagy and, to balance the number of mitochondria, new mitochondria are generated by biogenesis.
Figure 2. Figure 2. Parkin‐mediated mitophagy. In healthy mitochondria, PINK1 is degraded by MPP and PARL protease. When mitochondria are depolarized, PINK1 is stabilized and accumulated on the OMM. Stabilized PINK1 phosphorylates Mfn2 at Thr11 and Ser442 and recruits Parkin to the OMM. Alternatively, PINK1 phosphorylates ubiquitin and Parkin, thereby promoting the recruitment of Parkin to the OMM. In the cytosol, Parkin is deubiquitinated by USP8 and translocated to the OMM. BAG3 is translocated to the OMM with Parkin, whereas p53 prevents translocation of Parkin by direct interaction. On depolarized mitochondria, recruited Parkin ubiquitinates proteins on the OMM and promotes interaction between ubiquitinated OMM proteins and mitophagy adaptors, including p62, NBR1, and HDAC6, which have both a ubiquitin binding domain and an LC3‐interacting region. Finally, LC3 recruited by adaptor proteins facilitates mitophagy. Parkin‐mediated ubiquitination of OMM proteins can be reversed by USP15 and USP30. PINK1 also promotes localization of LC3 receptors, including optineurin, NDP52 and TAXBP1. LC3 receptors can recruit LC3 and facilitate mitophagy.
Figure 3. Figure 3. Parkin‐independent mitophagy. (A) Under hypoxic conditions, the OMM protein Bnip3 promotes mitophagy. Bnip3 and NIX have an LC3 binding region that allows direct interaction with LC3, and BclxL promotes this interaction. (B) Under basal conditions, Src and CK2 phosphorylate FUNDC1 at Tyr18 and Ser13respectively and inhibit its interaction with LC3. In response to hypoxia, ULK1 phosphorylates FUNDC1 at Ser17, and PGAM5 de‐phosphorylates FUNDC1 at Ser13, thus stimulating mitophagy. (C) The IMM protein cardiolipin translocates to the OMM upon mitochondrial injury and interacts with LC3 to promote mitophagy. When mitophagy is delayed, externalized cardiolipin undergoes peroxidation and promotes apoptosis. (D) A functional mammalian homolog of Atg32, Bcl2‐L‐13 has an LC3 interacting region and, like yeast Atg32, can promote mitochondrial fragmentation. Bcl2‐L‐13 localizes on the OMM and promotes mitophagy.
Figure 4. Figure 4. Mitophagy and cardiac diseases. (A) Under ischemic conditions, cardiac cellular energy rapidly decreases and metabolic pathways are interrupted. Due to reduced energy status, the level of mitochondrial Ca2+ is increased and mitochondrial membrane potential is reduced. Finally, dysfunctional mitochondria are accumulated in the ischemic heart. In this condition, Parkin‐mediated and FUNDC1‐mediated mitophagy act protectively. (B) Upon myocardial reperfusion, the level of cellular ROS is drastically increased and mitochondrial membrane potential is increased. This causes mPTP opening, thereby causing apoptosis and necrosis. In this condition, accumulated CO2 and bicarbonate inhibit mitophagy and promote myocardial injury. Drp1‐mediated and PGAM5‐mediated mitophagy acts as a protective process. (C) Pressure overload promotes mitochondrial dysfunction and inhibits the activity of DNase‐II, which degrades mitochondrial DNA in the lysosome. Thus, accumulated mitochondrial DNA activates TLR9‐dependent inflammation. Under pressure overload conditions, Drp1‐mediated mitophagy plays an essential role in protecting the heart. (D) In type 1 diabetes, accumulated glucose increases the level of mitochondrial O2•−. This enhances mitochondrial ROS, thus promoting myocardial cell death. A high level of glucose inhibits autophagy and, simultaneously, alternative autophagy and mitophagy are activated through a compensatory mechanism.


Figure 1. Mitochondrial quality control systems. During mitochondrial fusion, both Mfn1 and Mfn2 mediate OMM fusion while OPA1 simultaneously mediates IMM fusion. Membrane bounded L‐OPA1 can be cleaved to S‐OPA1 by YME1L and OMA1. The balance of between L‐OPA1 and S‐OPA1 affects mitochondrial fission and fusion. Mitochondrial fission is promoted by translocation of Drp1 to mitochondria. Translocation of Drp1 is mediated by Drp1 adaptors including MFF, MiD49, and Mid51. In addition, post‐translational modification of Drp1 regulates translocation of Drp1. Phosphorylation of Drp1 at Ser616 by Cdk1/cyclin B enhances Drp1 localization on the OMM. In contrast, phosphorylation of Drp1 at Ser637 by PKA facilitates Drp1 dissociation from the OMM. Mitochondrial Drp1 mediates fission by generating mechanical force. Depolarized mitochondria are selectively eliminated by mitophagy and, to balance the number of mitochondria, new mitochondria are generated by biogenesis.


Figure 2. Parkin‐mediated mitophagy. In healthy mitochondria, PINK1 is degraded by MPP and PARL protease. When mitochondria are depolarized, PINK1 is stabilized and accumulated on the OMM. Stabilized PINK1 phosphorylates Mfn2 at Thr11 and Ser442 and recruits Parkin to the OMM. Alternatively, PINK1 phosphorylates ubiquitin and Parkin, thereby promoting the recruitment of Parkin to the OMM. In the cytosol, Parkin is deubiquitinated by USP8 and translocated to the OMM. BAG3 is translocated to the OMM with Parkin, whereas p53 prevents translocation of Parkin by direct interaction. On depolarized mitochondria, recruited Parkin ubiquitinates proteins on the OMM and promotes interaction between ubiquitinated OMM proteins and mitophagy adaptors, including p62, NBR1, and HDAC6, which have both a ubiquitin binding domain and an LC3‐interacting region. Finally, LC3 recruited by adaptor proteins facilitates mitophagy. Parkin‐mediated ubiquitination of OMM proteins can be reversed by USP15 and USP30. PINK1 also promotes localization of LC3 receptors, including optineurin, NDP52 and TAXBP1. LC3 receptors can recruit LC3 and facilitate mitophagy.


Figure 3. Parkin‐independent mitophagy. (A) Under hypoxic conditions, the OMM protein Bnip3 promotes mitophagy. Bnip3 and NIX have an LC3 binding region that allows direct interaction with LC3, and BclxL promotes this interaction. (B) Under basal conditions, Src and CK2 phosphorylate FUNDC1 at Tyr18 and Ser13respectively and inhibit its interaction with LC3. In response to hypoxia, ULK1 phosphorylates FUNDC1 at Ser17, and PGAM5 de‐phosphorylates FUNDC1 at Ser13, thus stimulating mitophagy. (C) The IMM protein cardiolipin translocates to the OMM upon mitochondrial injury and interacts with LC3 to promote mitophagy. When mitophagy is delayed, externalized cardiolipin undergoes peroxidation and promotes apoptosis. (D) A functional mammalian homolog of Atg32, Bcl2‐L‐13 has an LC3 interacting region and, like yeast Atg32, can promote mitochondrial fragmentation. Bcl2‐L‐13 localizes on the OMM and promotes mitophagy.


Figure 4. Mitophagy and cardiac diseases. (A) Under ischemic conditions, cardiac cellular energy rapidly decreases and metabolic pathways are interrupted. Due to reduced energy status, the level of mitochondrial Ca2+ is increased and mitochondrial membrane potential is reduced. Finally, dysfunctional mitochondria are accumulated in the ischemic heart. In this condition, Parkin‐mediated and FUNDC1‐mediated mitophagy act protectively. (B) Upon myocardial reperfusion, the level of cellular ROS is drastically increased and mitochondrial membrane potential is increased. This causes mPTP opening, thereby causing apoptosis and necrosis. In this condition, accumulated CO2 and bicarbonate inhibit mitophagy and promote myocardial injury. Drp1‐mediated and PGAM5‐mediated mitophagy acts as a protective process. (C) Pressure overload promotes mitochondrial dysfunction and inhibits the activity of DNase‐II, which degrades mitochondrial DNA in the lysosome. Thus, accumulated mitochondrial DNA activates TLR9‐dependent inflammation. Under pressure overload conditions, Drp1‐mediated mitophagy plays an essential role in protecting the heart. (D) In type 1 diabetes, accumulated glucose increases the level of mitochondrial O2•−. This enhances mitochondrial ROS, thus promoting myocardial cell death. A high level of glucose inhibits autophagy and, simultaneously, alternative autophagy and mitophagy are activated through a compensatory mechanism.
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Teaching Material

J. Nah, S. Miyamoto, J. Sadoshima. Mitophagy as a Protective Mechanism against Myocardial Stress. Compr Physiol 7: 2017, 1407-1424. doi:10.1002/cphy.c170005

Didactic Synopsis

The information in this article will help with the teaching of the following specific topics at the graduate or advanced undergraduate level. We described how the structure and function of mitochondria are maintained in cardiomyocytes at baseline and in response to stress. The major teaching points are:

  • The quality of mitochondria in cells is maintained by well-coordinated actions of mitochondrial fission and fusion, mitophagy, and mitochondrial biogenesis.
  • A mitochondria-specific form of macroautophagy, namely, mitophagy, plays a major role in the degradation of mitochondria.
  • Mitochondrial depolarization activates PINK1, which in turn recruits Parkin to the outer mitochondrial membrane through phosphorylation of Mfn2 or Parkin, which turn recruits LC3 receptors/adapters and induces sequestration of damaged mitochondria by autophagosomes.
  • Although mitophagy is mediated primarily by PINK1-Parkin-dependent mechanisms, other alternative mechanisms exist to maintain the quality of mitochondria.
  • Cardiomyocytes have a high rate of mitophagy, which plays an important role in maintaining mitochondrial homeostasis in cardiomyocytes.
  • Mitophagy is activated during cardiac stress as a compensatory mechanism whereas insufficient activation of mitophagy leads to mitochondrial dysfunction and heart failure.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching Points: The quality of mitochondria is maintained by mitochondrial fusion, fission, mitophagy, and mitochondrial biogenesis. These four steps are mediated by distinct molecular mechanisms, but their activities are regulated in a coordinated manner through less well-characterized mechanisms. The goal of these processes is to maintain the level of healthy mitochondria.

Figure 2. Teaching Points: PINK1-Parkin-mediated mitophagy is one of the most well-characterized forms of mitophagy in many cell types. It is activated by mitochondrial depolarization, marks damaged mitochondria through polyubiquitination, and recruits receptors/adapters for LC3. These mechanisms allow damaged mitochondria to be selectively sequestrated by autophagosomes and transferred to lysosomes for degradation.

Figure 3. Teaching Points: Although PINK1-Parkin-mediated mitophagy is one of the most well-characterized mechanisms of mitophagy, there are many forms of autophagy which do not require Parkin.

Figure 4. Teaching Points: Mitophagy is activated by myocardial stress in many forms of heart disease. Activation of mitophagy in these conditions is generally protective and preserves mitochondrial function. Insufficient activation or downregulation of mitophagy induces mitochondrial dysfunction and leads to myocardial injury or heart failure.


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Article Title: Mitophagy as a Protective Mechanism against Myocardial Stress
 

How to Cite

Jihoon Nah, Shigeki Miyamoto, Junichi Sadoshima. Mitophagy as a Protective Mechanism against Myocardial Stress. Compr Physiol 2017, 7: 1407-1424. doi: 10.1002/cphy.c170005