title: Gamma rays induce a p53-independent mitochondrial biogenesis that is counter-regulated by HIF1α.
abstract: Mitochondrial biogenesis is an orchestrated process that presides to the regulation of the organelles homeostasis within a cell. We show that γ-rays, at doses commonly used in the radiation therapy for cancer treatment, induce an increase in mitochondrial mass and function, in response to a genotoxic stress that pushes cells into senescence, in the presence of a functional p53. Although the main effector of the response to γ-rays is the p53-p21 axis, we demonstrated that mitochondrial biogenesis is only indirectly regulated by p53, whose activation triggers a murine double minute 2 (MDM2)-mediated hypoxia-inducible factor 1α (HIF1α) degradation, leading to the release of peroxisome-proliferator activated receptor gamma co-activator 1β inhibition by HIF1α, thus promoting mitochondrial biogenesis. Mimicking hypoxia by HIF1α stabilization, in fact, blunts the mitochondrial response to γ-rays as well as the induction of p21-mediated cell senescence, indicating prevalence of the hypoxic over the genotoxic response. Finally, we also show in vivo that post-radiotherapy mitochondrial DNA copy number increase well correlates with lack of HIF1α increase in the tissue, concluding this may be a useful molecular tool to infer the trigger of a hypoxic response during radiotherapy, which may lead to failure of activation of cell senescence.
authors.affiliation: Medical Genetics Unit, Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Bartoletti-Stella
authors.forename: E
authors.initials: E
authors.lastname: Mariani
authors.forename: I
authors.initials: I
authors.lastname: Kurelac
authors.forename: A
authors.initials: A
authors.lastname: Maresca
authors.forename: M F
authors.initials: MF
authors.lastname: Caratozzolo
authors.forename: L
authors.initials: L
authors.lastname: Iommarini
authors.forename: V
authors.initials: V
authors.lastname: Carelli
authors.forename: L H
authors.initials: LH
authors.lastname: Eusebi
authors.forename: A
authors.initials: A
authors.lastname: Guido
authors.forename: G
authors.initials: G
authors.lastname: Cenacchi
authors.forename: L
authors.initials: L
authors.lastname: Fuccio
authors.forename: M
authors.initials: M
authors.lastname: Rugolo
authors.forename: A
authors.initials: A
authors.lastname: Tullo
authors.forename: A M
authors.initials: AM
authors.lastname: Porcelli
authors.forename: G
authors.initials: G
authors.lastname: Gasparre
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism; D048430:Cell Shape; D016922:Cellular Senescence; D056915:DNA Copy Number Variations; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D054629:Genome, Mitochondrial; D045325:HCT116 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism / Q000528:radiation effects*; D063269:Mitochondrial Turnover; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011401:Promoter Regions, Genetic; D055550:Protein Stability; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016601:RNA-Binding Proteins; D020218:Response Elements; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D004272:DNA, Mitochondrial; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C455622:PPARGC1B protein, human; D016601:RNA-Binding Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2