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

  • Brahimi-Horn MC Institute for Research on Cancer and Aging of Nice, CNRS-UMR 7284-INSERM U1081, University of Nice Sophia-Antipolis, Centre Antoine Lacassagne, Nice, France.
  • Lacas-Gervais S Centre Commun de Microscopie Appliquée, University of Nice Sophia-Antipolis, Nice, France.
  • Adaixo R Biozentrum, University of Basel, Basel, Switzerland.
  • Ilc K Institute for Research on Cancer and Aging of Nice, CNRS-UMR 7284-INSERM U1081, University of Nice Sophia-Antipolis, Centre Antoine Lacassagne, Nice, France.
  • Rouleau M Laboratoire de PhysioMédecine Moléculaire, UMR 7370 CNRS, University of Nice Sophia-Antipolis, Faculty of Medicine, Nice, France.
  • Notte A URBC-NARILIS, University of Namur, Namur, Belgium.
  • Dieu M URBC-NARILIS, University of Namur, Namur, Belgium.
  • Michiels C URBC-NARILIS, University of Namur, Namur, Belgium.
  • Voeltzel T Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS U5286, Centre Léon Bérard, Lyon, France.
  • Maguer-Satta V Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS U5286, Centre Léon Bérard, Lyon, France.
  • Pelletier J Institute for Research on Cancer and Aging of Nice, CNRS-UMR 7284-INSERM U1081, University of Nice Sophia-Antipolis, Centre Antoine Lacassagne, Nice, France.
  • Ilie M Institute 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.
  • Hofman P Institute 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.
  • Manoury B INSERM U1013, Hôpital Necker, Paris, France.
  • Schmidt A Biozentrum, University of Basel, Basel, Switzerland.
  • Hiller S Biozentrum, University of Basel, Basel, Switzerland.
  • Pouysségur J Institute 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.
  • Mazure NM Institute 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.
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  • 2015-02-19
Published in:
  • Molecular and cellular biology. - 2015
Adenocarcinoma
Adenocarcinoma of Lung
Animals
Cell Hypoxia
Cell Line
Cell Survival
HeLa Cells
Hep G2 Cells
Humans
Lung
Lung Neoplasms
Lysosomes
Membrane Proteins
Mice
Mitochondria
Proto-Oncogene Proteins
Tumor Suppressor Protein p53
Voltage-Dependent Anion Channel 1
English 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.
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  • English
Open access status
bronze
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https://sonar.ch/global/documents/91968
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