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Mitophagy and cancer.

Chourasia AH, Boland ML, Macleod KF - Cancer Metab (2015)

Bottom Line: Mitophagy is a selective form of macro-autophagy in which mitochondria are selectively targeted for degradation in autophagolysosomes.Mitophagy can have the beneficial effect of eliminating old and/or damaged mitochondria, thus maintaining the integrity of the mitochondrial pool.This prevents generation of reactive oxygen species and conserves valuable nutrients (such as oxygen) from being consumed inefficiently, thereby promoting cellular survival under conditions of energetic stress.

View Article: PubMed Central - PubMed

Affiliation: The Ben May Department for Cancer Research, The University of Chicago, 929 East 57th Street, Chicago, IL 60637 USA ; The Committee on Cancer Biology, The University of Chicago, 929 East 57th Street, Chicago, IL 60637 USA.

ABSTRACT
Mitophagy is a selective form of macro-autophagy in which mitochondria are selectively targeted for degradation in autophagolysosomes. Mitophagy can have the beneficial effect of eliminating old and/or damaged mitochondria, thus maintaining the integrity of the mitochondrial pool. However, mitophagy is not only limited to the turnover of dysfunctional mitochondria but also promotes reduction of overall mitochondrial mass in response to certain stresses, such as hypoxia and nutrient starvation. This prevents generation of reactive oxygen species and conserves valuable nutrients (such as oxygen) from being consumed inefficiently, thereby promoting cellular survival under conditions of energetic stress. The failure to properly modulate mitochondrial turnover in response to oncogenic stresses has been implicated both positively and negatively in tumorigenesis, while the potential of targeting mitophagy specifically as opposed to autophagy in general as a therapeutic strategy remains to be explored. The challenges and opportunities that come with our heightened understanding of the role of mitophagy in cancer are reviewed here.

No MeSH data available.


Related in: MedlinePlus

Parkin recruitment to depolarized mitochondria promotes their degradation by mitophagy. In polarized mitochondria, PINK1 is degraded in the mitochondrial matrix (left), but upon membrane depolarization, PINK1 is stabilized and accumulates at the OMM, where it phosphorylates Mfn-2 and other substrates, including ubiquitin, that act as receptors for Parkin. Once Parkin is recruited to the OMM, it ubiquitinates key protein substrates including VDAC1 and Mfn-2, and other possibly unknown targets (substrate X). Parkin-dependent ubiquitination of VDAC1 and other mitochondrial proteins promotes interaction with p62/Sqstm1 that in turn facilitates interaction with LC3 at nascent phagophores thereby targeting depolarized mitochondria for degradation by autophagy.
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Fig1: Parkin recruitment to depolarized mitochondria promotes their degradation by mitophagy. In polarized mitochondria, PINK1 is degraded in the mitochondrial matrix (left), but upon membrane depolarization, PINK1 is stabilized and accumulates at the OMM, where it phosphorylates Mfn-2 and other substrates, including ubiquitin, that act as receptors for Parkin. Once Parkin is recruited to the OMM, it ubiquitinates key protein substrates including VDAC1 and Mfn-2, and other possibly unknown targets (substrate X). Parkin-dependent ubiquitination of VDAC1 and other mitochondrial proteins promotes interaction with p62/Sqstm1 that in turn facilitates interaction with LC3 at nascent phagophores thereby targeting depolarized mitochondria for degradation by autophagy.

Mentions: The localization of the Parkin E3 ubiquitin ligase to the mitochondria is regulated by the PINK1 (PTEN-induced putative kinase 1) serine/threonine kinase that undergoes voltage-dependent import leading to proteolysis at the inner mitochondrial membrane in healthy mitochondria but accumulates at the outer mitochondrial membrane in response to mitochondrial depolarization [20,21,22,38] (Figure 1). PINK1 phosphorylates Parkin directly but mutation of all serine and threonine residues in Parkin did not block its translocation to the mitochondria [39], and recent evidence shows that PINK1 phosphorylation of ubiquitin on serine 65 is required to recruit Parkin to mitochondria [39,40]. A large number of mitochondrial proteins have been identified as Parkin substrates at the OMM, including Vdac1, Miro, and Mfn-2 [15,41-43], and indeed systematic identification of all Parkin substrates indicates that the mitochondrial proteome is markedly altered by Parkin activity [43]. Specific targets such as Mfn-2 are phosphorylated by PINK1 at the OMM, and Mfn-2 has been shown to selectively recruit Parkin to damaged mitochondria [44]. However, the wide range of mitochondrial substrates that are ubiquitinated and then phosphorylated by PINK1 suggests that Mfn-2 may be only one of many receptors for Parkin at the mitochondria [43,39]. Furthermore, targeting of mitochondrial substrates by Parkin is highly dynamic [43] with the role of mitochondrial deubiquitinases such as USP30 in antagonizing Parkin-dependent mitophagy recently emerging [45] and suggesting that additional signaling inputs modulate Parkin’s role in mitophagy in response to stress.Figure 1


Mitophagy and cancer.

Chourasia AH, Boland ML, Macleod KF - Cancer Metab (2015)

Parkin recruitment to depolarized mitochondria promotes their degradation by mitophagy. In polarized mitochondria, PINK1 is degraded in the mitochondrial matrix (left), but upon membrane depolarization, PINK1 is stabilized and accumulates at the OMM, where it phosphorylates Mfn-2 and other substrates, including ubiquitin, that act as receptors for Parkin. Once Parkin is recruited to the OMM, it ubiquitinates key protein substrates including VDAC1 and Mfn-2, and other possibly unknown targets (substrate X). Parkin-dependent ubiquitination of VDAC1 and other mitochondrial proteins promotes interaction with p62/Sqstm1 that in turn facilitates interaction with LC3 at nascent phagophores thereby targeting depolarized mitochondria for degradation by autophagy.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4373087&req=5

Fig1: Parkin recruitment to depolarized mitochondria promotes their degradation by mitophagy. In polarized mitochondria, PINK1 is degraded in the mitochondrial matrix (left), but upon membrane depolarization, PINK1 is stabilized and accumulates at the OMM, where it phosphorylates Mfn-2 and other substrates, including ubiquitin, that act as receptors for Parkin. Once Parkin is recruited to the OMM, it ubiquitinates key protein substrates including VDAC1 and Mfn-2, and other possibly unknown targets (substrate X). Parkin-dependent ubiquitination of VDAC1 and other mitochondrial proteins promotes interaction with p62/Sqstm1 that in turn facilitates interaction with LC3 at nascent phagophores thereby targeting depolarized mitochondria for degradation by autophagy.
Mentions: The localization of the Parkin E3 ubiquitin ligase to the mitochondria is regulated by the PINK1 (PTEN-induced putative kinase 1) serine/threonine kinase that undergoes voltage-dependent import leading to proteolysis at the inner mitochondrial membrane in healthy mitochondria but accumulates at the outer mitochondrial membrane in response to mitochondrial depolarization [20,21,22,38] (Figure 1). PINK1 phosphorylates Parkin directly but mutation of all serine and threonine residues in Parkin did not block its translocation to the mitochondria [39], and recent evidence shows that PINK1 phosphorylation of ubiquitin on serine 65 is required to recruit Parkin to mitochondria [39,40]. A large number of mitochondrial proteins have been identified as Parkin substrates at the OMM, including Vdac1, Miro, and Mfn-2 [15,41-43], and indeed systematic identification of all Parkin substrates indicates that the mitochondrial proteome is markedly altered by Parkin activity [43]. Specific targets such as Mfn-2 are phosphorylated by PINK1 at the OMM, and Mfn-2 has been shown to selectively recruit Parkin to damaged mitochondria [44]. However, the wide range of mitochondrial substrates that are ubiquitinated and then phosphorylated by PINK1 suggests that Mfn-2 may be only one of many receptors for Parkin at the mitochondria [43,39]. Furthermore, targeting of mitochondrial substrates by Parkin is highly dynamic [43] with the role of mitochondrial deubiquitinases such as USP30 in antagonizing Parkin-dependent mitophagy recently emerging [45] and suggesting that additional signaling inputs modulate Parkin’s role in mitophagy in response to stress.Figure 1

Bottom Line: Mitophagy is a selective form of macro-autophagy in which mitochondria are selectively targeted for degradation in autophagolysosomes.Mitophagy can have the beneficial effect of eliminating old and/or damaged mitochondria, thus maintaining the integrity of the mitochondrial pool.This prevents generation of reactive oxygen species and conserves valuable nutrients (such as oxygen) from being consumed inefficiently, thereby promoting cellular survival under conditions of energetic stress.

View Article: PubMed Central - PubMed

Affiliation: The Ben May Department for Cancer Research, The University of Chicago, 929 East 57th Street, Chicago, IL 60637 USA ; The Committee on Cancer Biology, The University of Chicago, 929 East 57th Street, Chicago, IL 60637 USA.

ABSTRACT
Mitophagy is a selective form of macro-autophagy in which mitochondria are selectively targeted for degradation in autophagolysosomes. Mitophagy can have the beneficial effect of eliminating old and/or damaged mitochondria, thus maintaining the integrity of the mitochondrial pool. However, mitophagy is not only limited to the turnover of dysfunctional mitochondria but also promotes reduction of overall mitochondrial mass in response to certain stresses, such as hypoxia and nutrient starvation. This prevents generation of reactive oxygen species and conserves valuable nutrients (such as oxygen) from being consumed inefficiently, thereby promoting cellular survival under conditions of energetic stress. The failure to properly modulate mitochondrial turnover in response to oncogenic stresses has been implicated both positively and negatively in tumorigenesis, while the potential of targeting mitophagy specifically as opposed to autophagy in general as a therapeutic strategy remains to be explored. The challenges and opportunities that come with our heightened understanding of the role of mitophagy in cancer are reviewed here.

No MeSH data available.


Related in: MedlinePlus