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Published on: August 12, 2018
Mitochondrial survivin reduces oxidative phosphorylation in cancer cells by inhibiting mitophagy
Amelia R Townley1, Sally P Wheatley2
1School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK.
Abstract:
Survivin (also known as BIRC5) is a cancer-associated protein that is pivotal for cellular life and death - it is an essential mitotic protein and an inhibitor of apoptosis. In cancer cells, a small pool of survivin localises to the mitochondria, the function of which remains to be elucidated. Here, we report that mitochondrial survivin inhibits the selective form of autophagy called 'mitophagy', causing an accumulation of respiratory-defective mitochondria. Mechanistically, the data reveal that survivin prevents recruitment of the E3-ubiquitin ligase Parkin to mitochondria and their subsequent recognition by the autophagosome. The data also demonstrate that cells in which mitophagy has been blocked by survivin expression have an increased dependency on glycolysis. As these effects were found exclusively in cancer cells, they suggest that the primary act of mitochondrial survivin is to steer cells towards the implementation of the Warburg transition by inhibiting mitochondrial turnover, which enables them to adapt and survive.This article has an associated First Person interview with the first author of the paper.
Insights
Mitochondrial survivin protein inhibits mitophagy, leading to defective mitochondria accumulation in cancer cells. This process promotes cancer cell adaptation and survival by increasing reliance on glycolysis.
Area of Science:
- Cell Biology
- Cancer Biology
- Biochemistry
Background:
- Survivin (BIRC5) is a key protein regulating cell death and mitosis.
- A subset of survivin localizes to mitochondria in cancer cells, with its function unclear.
- Autophagy, particularly mitophagy, is crucial for mitochondrial quality control.
Purpose of the Study:
- To investigate the role of mitochondrial survivin in cancer cells.
- To elucidate the mechanism by which mitochondrial survivin affects cellular processes.
- To understand the implications of mitochondrial survivin's function for cancer metabolism and survival.
Main Methods:
- Investigated survivin's localization and function in cancer cells.
- Utilized techniques to study mitophagy and mitochondrial function.
- Analyzed cellular metabolic changes, including glycolysis and mitochondrial respiration.
Main Results:
- Mitochondrial survivin was found to inhibit mitophagy, preventing the removal of damaged mitochondria.
- Survivin blocks the recruitment of Parkin to mitochondria, a key step in mitophagy.
- Inhibition of mitophagy by survivin leads to an accumulation of dysfunctional mitochondria and increased glycolysis.
- These effects were specific to cancer cells.
Conclusions:
- Mitochondrial survivin plays a critical role in cancer cell adaptation by inhibiting mitophagy.
- This inhibition promotes metabolic reprogramming towards glycolysis (Warburg effect).
- Survivin's action on mitophagy provides a mechanism for cancer cells to survive and adapt by maintaining dysfunctional mitochondria.
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