Local mitochondrial-endolysosomal microfusion cleaves voltage- dependent anion channel 1 to promote survival in hypoxia

M. Christiane Brahimi-Horn, Sandra Lacas-Gervais, Ricardo Adaixo, Karine Ilc, Matthieu Rouleau, Annick Notte, Marc Dieu, Carine Michiels, Thibault Voeltzel, Véronique Maguer-Satta, Joffrey Pelletier, Marius Ilie, Paul Hofman, Bénédicte Manoury, Alexander Schmidt, Sebastian Hiller, Jacques Pouysségur, Nathalie M. Mazure

Research output: Contribution to journalArticlepeer-review

253 Downloads (Pure)


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.

Original languageEnglish
Pages (from-to)1491-1505
Number of pages15
JournalMolecular Cell Biology
Issue number9
Publication statusPublished - 2015

Cite this