Abstract
The oxygen-limiting (hypoxic) microenvironment of tumors induces metabolic reprogramming and cell survival, but the underlying mechanisms involving mitochondria remain poorly understood. We previously demonstrated that hypoxia-inducible factor 1 mediates the hyperfusion of mitochondria by inducing Bcl-2/adenovirus E1B 19-kDa interacting protein 3 and posttranslational truncation of the mitochondrial ATP transporter outer membrane voltage-dependent anion channel 1 in hypoxic cells. In addition, we showed that truncation is associated with increased resistance to drug-induced apoptosis and is indicative of increased patient chemoresistance. We now show that silencing of the tumor suppressor TP53 decreases truncation and increases drug-induced apoptosis. We also show that TP53 regulates truncation through induction of the mitochondrial protein Mieap. While we found that truncation was independent of mitophagy, we observed local microfusion between mitochondria and endolysosomes in hypoxic cells in culture and in patients' tumor tissues. Since we found that the endolysosomal asparagine endopeptidase was responsible for truncation, we propose that it is a readout of mitochondrial-endolysosomal microfusion in hypoxia. These novel findings provide the framework for a better understanding of hypoxic cell metabolism and cell survival through mitochondrial-endolysosomal microfusion regulated by hypoxia-inducible factor 1 and TP53.
Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01402-14.
ACKNOWLEDGMENTS
We thank C Pierreux (de Duve Institute, UC Louvain, Louvain, Belgium) for his help with HaloTag protein purification and G. Chinnadurai (Saint Louis University Health Sciences Center, St. Louis, MO) for providing the HA-BNIP3 cDNA-containing plasmid.
This research was supported by grants from the Fondation ARC, Fondation de France, ANR, INCA, la Ligue Nationale Contre le Cancer (Équipe Labelisée LNCC), METOXIA and MOMP (FP7-EU programs), MRT, and Canceropôle PACA. The Institute for Research on Cancer and Aging of Nice is funded by the Centre A. Lacassagne, CNRS, and INSERM.
The funders had no role in study design, data collection and analysis, the decision to publish, or preparation of the manuscript. We disclose no potential conflicts of interest.
The authors' contributions are as follows: conception and design, M. C. Brahimi-Horn and N. M. Mazure; development of methodology, M. C. Brahimi-Horn, C. Michiels, S. Hiller, and N. M. Mazure; acquisition of data (acquired and managed patients, provided facilities, etc.), S. Lacas-Gervais, R. Adaixo, K. Ilc, M. Rouleau, A. Notte, M. Dieu, T. Voeltzel, V. Maguer-Satta, M. Ilie, P. Hofman, and A. Schmidt; analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis), M. C. Brahimi-Horn, S. Lacas-Gervais, A. Schmidt, S. Hiller, and N. M. Mazure; writing, review, and/or revision of the manuscript, M. C. Brahimi-Horn, J. Pouysségur, and N. M. Mazure; technical or material support, J. Pelletier and B. Manoury; and study supervision, N. M. Mazure.