title: Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells.
abstract: Alterations of mitochondrial metabolism and genomic instability have been implicated in tumorigenesis in multiple tissues. High-grade glioma (HGG), one of the most lethal human neoplasms, displays genetic modifications of Krebs cycle components as well as electron transport chain (ETC) alterations. Furthermore, the p53 tumor suppressor, which has emerged as a key regulator of mitochondrial respiration at the expense of glycolysis, is genetically inactivated in a large proportion of HGG cases. Therefore, it is becoming evident that genetic modifications can affect cell metabolism in HGG; however, it is currently unclear whether mitochondrial metabolism alterations could vice versa promote genomic instability as a mechanism for neoplastic transformation. Here, we show that, in neural progenitor/stem cells (NPCs), which can act as HGG cell of origin, inhibition of mitochondrial metabolism leads to p53 genetic inactivation. Impairment of respiration via inhibition of complex I or decreased mitochondrial DNA copy number leads to p53 genetic loss and a glycolytic switch. p53 genetic inactivation in ETC-impaired neural stem cells is caused by increased reactive oxygen species and associated oxidative DNA damage. ETC-impaired cells display a marked growth advantage in the presence or absence of oncogenic RAS, and form undifferentiated tumors when transplanted into the mouse brain. Finally, p53 mutations correlated with alterations in ETC subunit composition and activity in primary glioma-initiating neural stem cells. Together, these findings provide previously unidentified insights into the relationship between mitochondria, genomic stability, and tumor suppressive control, with implications for our understanding of brain cancer pathogenesis.
authors.affiliation: Samantha Dickson Brain Cancer Unit, University College London Cancer Institute, London WC1E 6BT, United Kingdom;
authors.forename: Stefano
authors.initials: S
authors.lastname: Bartesaghi
authors.affiliation: Samantha Dickson Brain Cancer Unit, University College London Cancer Institute, London WC1E 6BT, United Kingdom; Department of Experimental and Clinical Sciences, Aging Research Center (Centro Scienze dell'Invecchiamento), University G. d'Annunzio, 66013 Chieti-Pescara, Italy;
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Graziano
authors.affiliation: Samantha Dickson Brain Cancer Unit, University College London Cancer Institute, London WC1E 6BT, United Kingdom;
authors.forename: Sara
authors.initials: S
authors.lastname: Galavotti
authors.affiliation: Institute of Neurology, University College London, London WC1N 3BG, United Kingdom;
authors.forename: Nick V
authors.initials: NV
authors.lastname: Henriquez
authors.affiliation: Samantha Dickson Brain Cancer Unit, University College London Cancer Institute, London WC1E 6BT, United Kingdom;
authors.forename: Joanne
authors.initials: J
authors.lastname: Betts
authors.affiliation: Samantha Dickson Brain Cancer Unit, University College London Cancer Institute, London WC1E 6BT, United Kingdom;
authors.forename: Jayeta
authors.initials: J
authors.lastname: Saxena
authors.forename: Valentina
authors.initials: V
authors.lastname: Minieri
authors.affiliation: Samantha Dickson Brain Cancer Unit, University College London Cancer Institute, London WC1E 6BT, United Kingdom;
authors.forename: Deli
authors.initials: D
authors.lastname: A
authors.affiliation: Karolinska Institute, SE-171 77 Stockholm, Sweden;
authors.forename: Anna
authors.initials: A
authors.lastname: Karlsson
authors.affiliation: Medical Research Council Toxicology Unit, Leicester LE1 7HB, United Kingdom;
authors.forename: L Miguel
authors.initials: LM
authors.lastname: Martins
authors.affiliation: Barts Cancer Institute, Queen Mary University, London E1 2AD, United Kingdom; and.
authors.forename: Melania
authors.initials: M
authors.lastname: Capasso
authors.affiliation: Deutsches Zentrum für Neurodegenerative Erkrankungen, 53175 Bonn, Germany.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Nicotera
authors.affiliation: Institute of Neurology, University College London, London WC1N 3BG, United Kingdom;
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandner
authors.affiliation: Department of Experimental and Clinical Sciences, Aging Research Center (Centro Scienze dell'Invecchiamento), University G. d'Annunzio, 66013 Chieti-Pescara, Italy;
authors.forename: Vincenzo
authors.initials: V
authors.lastname: De Laurenzi
authors.affiliation: Samantha Dickson Brain Cancer Unit, University College London Cancer Institute, London WC1E 6BT, United Kingdom; p.salomoni@ucl.ac.uk.
authors.forename: Paolo
authors.initials: P
authors.lastname: Salomoni
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002952:Citric Acid Cycle / Q000235:genetics; D004249:DNA Damage; D045222:Electron Transport Chain Complex Proteins / Q000235:genetics / Q000378:metabolism; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D045222:Electron Transport Chain Complex Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: brain cancer; mitochondrial metabolism; p53