Abstract

Mitochondrial biogenesis is an orchestrated process that presides to the regulation of the organelles homeostasis within a cell. We show that ?-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 ?-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 1? (HIF1?) degradation, leading to the release of peroxisome-proliferator activated receptor gamma co-activator 1? inhibition by HIF1?, thus promoting mitochondrial biogenesis. Mimicking hypoxia by HIF1? stabilization, in fact, blunts the mitochondrial response to ?-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 HIF1? 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.

Autore Pugliese

• Tullo Apollonia , Caratozzolo Mariano Francesco

Tutti gli autori

• Bartoletti-Stella A.; Mariani E.; Kurelac I.; Maresca A.; Caratozzolo M.F.; Iommarini L.; Carelli V.; Eusebi L.H.; Guido A.; Cenacchi G.; Fuccio L.; Rugolo M.; Tullo A.; Porcelli A.M.; Gasparre G.

Titolo volume/Rivista

Cell death and disease

Anno di pubblicazione

2013

ISSN

2041-4889

ISBN

Non Disponibile

Numero di citazioni Wos

Nessuna citazione

Ultimo Aggiornamento Citazioni

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Numero di citazioni Scopus

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Ultimo Aggiornamento Citazioni

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Settori ERC

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Codici ASJC

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