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Mol Cell Biol. 2015 May;35(9):1491-505. doi: 10.1128/MCB.01402-14. Epub 2015 Feb 17.

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

Author information

  • 1Institute for Research on Cancer and Aging of Nice, CNRS-UMR 7284-INSERM U1081, University of Nice Sophia-Antipolis, Centre Antoine Lacassagne, Nice, France.
  • 2Centre Commun de Microscopie Appliquée, University of Nice Sophia-Antipolis, Nice, France.
  • 3Biozentrum, University of Basel, Basel, Switzerland.
  • 4Laboratoire de PhysioMédecine Moléculaire, UMR 7370 CNRS, University of Nice Sophia-Antipolis, Faculty of Medicine, Nice, France.
  • 5URBC-NARILIS, University of Namur, Namur, Belgium.
  • 6Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS U5286, Centre Léon Bérard, Lyon, France.
  • 7Institute for Research on Cancer and Aging of Nice, CNRS-UMR 7284-INSERM U1081, University of Nice Sophia-Antipolis, Centre Antoine Lacassagne, Nice, France Human Tissue Biobank Unit/CRB and Laboratory of Clinical and Experimental Pathology, Louis Pasteur Hospital, Nice, France.
  • 8INSERM U1013, Hôpital Necker, Paris, France.
  • 9Institute for Research on Cancer and Aging of Nice, CNRS-UMR 7284-INSERM U1081, University of Nice Sophia-Antipolis, Centre Antoine Lacassagne, Nice, France Centre Scientifique de Monaco (CSM), Monaco.
  • 10Institute for Research on Cancer and Aging of Nice, CNRS-UMR 7284-INSERM U1081, University of Nice Sophia-Antipolis, Centre Antoine Lacassagne, Nice, France Nathalie.Mazure@unice.fr.

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.

PMID:
25691661
PMCID:
PMC4387213
DOI:
10.1128/MCB.01402-14
[PubMed - indexed for MEDLINE]
Free PMC Article
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