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.

Bartoletti-Stella A, Mariani E, Kurelac I, Maresca A, Caratozzolo MF, Iommarini L, et al. (2013). Gamma rays induce a p53-independent mitochondrial biogenesis that is counter-regulated by HIF1α. CELL DEATH & DISEASE, 4, 1-11 [10.1038/cddis.2013.187].

Gamma rays induce a p53-independent mitochondrial biogenesis that is counter-regulated by HIF1α.

MARIANI, ELISA;KURELAC, IVANA;MARESCA, ALESSANDRA;IOMMARINI, LUISA;CARELLI, VALERIO;EUSEBI, LEONARDO HENRY UMBERTO;CENACCHI, GIOVANNA;FUCCIO, LORENZO;RUGOLO, MICHELA;PORCELLI, ANNA MARIA;GASPARRE, GIUSEPPE
2013

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.
2013
Bartoletti-Stella A, Mariani E, Kurelac I, Maresca A, Caratozzolo MF, Iommarini L, et al. (2013). Gamma rays induce a p53-independent mitochondrial biogenesis that is counter-regulated by HIF1α. CELL DEATH & DISEASE, 4, 1-11 [10.1038/cddis.2013.187].
Bartoletti-Stella A;Mariani E;Kurelac I;Maresca A;Caratozzolo MF;Iommarini L;Carelli V;Eusebi LH;Guido A;Cenacchi G;Fuccio L;Rugolo M;Tullo A;Porcelli...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/145946
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