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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

Strategies to target mitophagy for cancer therapy. Tumor cells are likely to be more dependent on functional mitophagy than normal cells due the increased requirement to manage ROS levels, due to dependence on key aspects of mitochondrial metabolism, such as glutaminolysis, particularly given the ischemic nature of advanced macroscopic tumors. Such a dependence on mitophagy could be exploited therapeutically by the development of specific small molecule inhibitors of mitophagy that could be combined with other drugs that induce mitochondrial dysfunction, such as respiratory inhibitors or antibiotics, to further increase the requirement for functional mitophagy.
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Fig3: Strategies to target mitophagy for cancer therapy. Tumor cells are likely to be more dependent on functional mitophagy than normal cells due the increased requirement to manage ROS levels, due to dependence on key aspects of mitochondrial metabolism, such as glutaminolysis, particularly given the ischemic nature of advanced macroscopic tumors. Such a dependence on mitophagy could be exploited therapeutically by the development of specific small molecule inhibitors of mitophagy that could be combined with other drugs that induce mitochondrial dysfunction, such as respiratory inhibitors or antibiotics, to further increase the requirement for functional mitophagy.

Mentions: The adverse tumor-promoting effects of chronic mitophagy inhibition arising from deletion or inactivation of genes such as Parkin and BNip3, particularly induction of the Warburg effect, argue against targeting mitophagy as a therapeutic strategy. However, for advanced tumors that have already undergone the switch to glycolytic metabolism but remain dependent on mitochondria for other metabolic functions, such as glutaminolysis, fatty acid oxidation, and generation of critical Krebs cycle intermediates, acute chemical inhibition of mitophagy remains a valid approach to be tested therapeutically. Since tumor cells already produce increased ROS compared to normal cells [118], the combined effect of further increased ROS and reduced mitochondrial metabolism arising from inhibition of mitophagy may be synergistic and promote efficient tumor cell killing while sparing normal cells that are less likely to have dysfunctional mitochondria and therefore likely to be less sensitive to mitophagy inhibition (FigureĀ 3). Before such approaches can be adopted though, it will be necessary to investigate further how much mitochondrial damage or dysfunction can be tolerated by normal versus tumor cells, and for how long, before loss of viability. Once mitophagy is inhibited, for example, it is not clear how rapidly damaged mitochondria accumulate and to what extent this varies depending on cell type, the specific type of mitochondrial damage sustained, the nature of the damaging stress applied, or indeed the ability of the cell to adapt to mitochondrial dysfunction in other ways. For example, increased mitochondrial fusion may allow some cell types to distribute damaged mitochondrial content in such a way that cells can survive mitophagy inhibition. It will also be important to identify which tumors retain the capacity to undergo functional mitophagy and have not undergone selection for mitophagy inactivation through deletion of Parkin, or silencing of BNIP3, for example.Figure 3


Mitophagy and cancer.

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

Strategies to target mitophagy for cancer therapy. Tumor cells are likely to be more dependent on functional mitophagy than normal cells due the increased requirement to manage ROS levels, due to dependence on key aspects of mitochondrial metabolism, such as glutaminolysis, particularly given the ischemic nature of advanced macroscopic tumors. Such a dependence on mitophagy could be exploited therapeutically by the development of specific small molecule inhibitors of mitophagy that could be combined with other drugs that induce mitochondrial dysfunction, such as respiratory inhibitors or antibiotics, to further increase the requirement for functional mitophagy.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig3: Strategies to target mitophagy for cancer therapy. Tumor cells are likely to be more dependent on functional mitophagy than normal cells due the increased requirement to manage ROS levels, due to dependence on key aspects of mitochondrial metabolism, such as glutaminolysis, particularly given the ischemic nature of advanced macroscopic tumors. Such a dependence on mitophagy could be exploited therapeutically by the development of specific small molecule inhibitors of mitophagy that could be combined with other drugs that induce mitochondrial dysfunction, such as respiratory inhibitors or antibiotics, to further increase the requirement for functional mitophagy.
Mentions: The adverse tumor-promoting effects of chronic mitophagy inhibition arising from deletion or inactivation of genes such as Parkin and BNip3, particularly induction of the Warburg effect, argue against targeting mitophagy as a therapeutic strategy. However, for advanced tumors that have already undergone the switch to glycolytic metabolism but remain dependent on mitochondria for other metabolic functions, such as glutaminolysis, fatty acid oxidation, and generation of critical Krebs cycle intermediates, acute chemical inhibition of mitophagy remains a valid approach to be tested therapeutically. Since tumor cells already produce increased ROS compared to normal cells [118], the combined effect of further increased ROS and reduced mitochondrial metabolism arising from inhibition of mitophagy may be synergistic and promote efficient tumor cell killing while sparing normal cells that are less likely to have dysfunctional mitochondria and therefore likely to be less sensitive to mitophagy inhibition (FigureĀ 3). Before such approaches can be adopted though, it will be necessary to investigate further how much mitochondrial damage or dysfunction can be tolerated by normal versus tumor cells, and for how long, before loss of viability. Once mitophagy is inhibited, for example, it is not clear how rapidly damaged mitochondria accumulate and to what extent this varies depending on cell type, the specific type of mitochondrial damage sustained, the nature of the damaging stress applied, or indeed the ability of the cell to adapt to mitochondrial dysfunction in other ways. For example, increased mitochondrial fusion may allow some cell types to distribute damaged mitochondrial content in such a way that cells can survive mitophagy inhibition. It will also be important to identify which tumors retain the capacity to undergo functional mitophagy and have not undergone selection for mitophagy inactivation through deletion of Parkin, or silencing of BNIP3, for example.Figure 3

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