title: Local mitochondrial-endolysosomal microfusion cleaves voltage-dependent anion channel 1 to promote survival in hypoxia.
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.
authors.affiliation: Institute for Research on Cancer and Aging of Nice, CNRS-UMR 7284-INSERM U1081, University of Nice Sophia-Antipolis, Centre Antoine Lacassagne, Nice, France.
authors.forename: M Christiane
authors.initials: MC
authors.lastname: Brahimi-Horn
authors.affiliation: Centre Commun de Microscopie Appliquée, University of Nice Sophia-Antipolis, Nice, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Lacas-Gervais
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Adaixo
authors.affiliation: Institute for Research on Cancer and Aging of Nice, CNRS-UMR 7284-INSERM U1081, University of Nice Sophia-Antipolis, Centre Antoine Lacassagne, Nice, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Ilc
authors.affiliation: Laboratoire de PhysioMédecine Moléculaire, UMR 7370 CNRS, University of Nice Sophia-Antipolis, Faculty of Medicine, Nice, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Rouleau
authors.affiliation: URBC-NARILIS, University of Namur, Namur, Belgium.
authors.forename: Annick
authors.initials: A
authors.lastname: Notte
authors.affiliation: URBC-NARILIS, University of Namur, Namur, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Dieu
authors.affiliation: URBC-NARILIS, University of Namur, Namur, Belgium.
authors.forename: Carine
authors.initials: C
authors.lastname: Michiels
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS U5286, Centre Léon Bérard, Lyon, France.
authors.forename: Thibault
authors.initials: T
authors.lastname: Voeltzel
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS U5286, Centre Léon Bérard, Lyon, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Maguer-Satta
authors.affiliation: Institute for Research on Cancer and Aging of Nice, CNRS-UMR 7284-INSERM U1081, University of Nice Sophia-Antipolis, Centre Antoine Lacassagne, Nice, France.
authors.forename: Joffrey
authors.initials: J
authors.lastname: Pelletier
authors.affiliation: 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.
authors.forename: Marius
authors.initials: M
authors.lastname: Ilie
authors.affiliation: 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.
authors.forename: Paul
authors.initials: P
authors.lastname: Hofman
authors.affiliation: INSERM U1013, Hôpital Necker, Paris, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Manoury
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Schmidt
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Hiller
authors.affiliation: 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.
authors.forename: Jacques
authors.initials: J
authors.lastname: Pouysségur
authors.affiliation: 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.
authors.forename: Nathalie M
authors.initials: NM
authors.lastname: Mazure
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D015687:Cell Hypoxia; D002460:Cell Line; D002470:Cell Survival; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D050995:Voltage-Dependent Anion Channel 1 / Q000032:analysis / Q000378:metabolism*
chemical_list: C090121:BNIP3 protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C494762:VDAC1 protein, human; D050995:Voltage-Dependent Anion Channel 1