Abstract
The p53-inducible BH3-only protein PUMA is a key mediator of p53-dependent apoptosis, and PUMA has been shown to function by activating Bax and mitochondrial outer membrane permeabilization. In this study, we describe an ability of PUMA to induce autophagy that leads to the selective removal of mitochondria. This function of PUMA depends on Bax/Bak and can be reproduced by overexpression of Bax. The induction of autophagy coincides with cytochrome c release, and taken together the results suggest that PUMA functions through Bax to induce mitochondrial autophagy in response to mitochondrial perturbations. Surprisingly, inhibition of PUMA or Bax-induced autophagy dampens the apoptotic response, suggesting that under some circumstances the selective targeting of mitochondria for autophagy can enhance apoptosis.
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Abbreviations
- MOMP:
-
mitochondrial outer membrane potential
- BH3:
-
bcl2 homology 3
- ROS:
-
reactive oxygen species
- z-VAD-fmk:
-
benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone
- LC3:
-
(microtubule-associated protein 1) light chain 3
- MEF:
-
mouse embryo fibroblast
- ER:
-
endoplasmic reticulum
- MPT:
-
mitochondria permeability transiition
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Acknowledgements
We thank Dr. Aviva Tolkovsky (University of Cambridge) for the kind gift of GFP-LC3-expressing adenovirus. This work was funded by Cancer Research UK and the West of Scotland Women's Bowling Association.
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Supplementary Information accompanies the paper on Cell Death and Differentiation website (http://www.nature.com/cdd)
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Yee, K., Wilkinson, S., James, J. et al. PUMA- and Bax-induced autophagy contributes to apoptosis. Cell Death Differ 16, 1135–1145 (2009). https://doi.org/10.1038/cdd.2009.28
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DOI: https://doi.org/10.1038/cdd.2009.28
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