Upon massive DNA damage, hyperactivation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP)-1 causes severe depletion of intracellular NAD and ATP pools as well as mitochondrial dysfunction. Thus far, the molecular mechanisms contributing to PARP-1-dependent impairment of mitochondrial functioning have not been identified. We found that degradation of the PARP-1 product poly(ADP-ribose) through the concerted actions of poly(ADP-ribose) glycohydrolase and NUDIX (nucleoside diphosphate-X) hydrolases leads to accumulation of AMP. The latter, in turn, inhibits the ADP/ATP translocator, prompting mitochondrial energy failure. For the first time, our findings identify NUDIX hydrolases as key enzymes involved in energy derangement during PARP-1 hyperactivity. Also, these data disclose unanticipated AMP-dependent impairment of mitochondrial exchange of adenine nucleotides, which can be of relevance to organelle functioning and disease pathogenesis.

Poly(ADP-ribose) catabolism triggers AMP-dependent mitochondrial energy failure / L. Formentini; A. Macchiarulo; G. Cipriani; E. Camaioni; E. Rapizzi; R. Pellicciari; F. Moroni; A. Chiarugi. - In: THE JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 1067-8816. - STAMPA. - 284(2009), pp. 17668-17679.

Poly(ADP-ribose) catabolism triggers AMP-dependent mitochondrial energy failure

FORMENTINI, LAURA;RAPIZZI, ELENA;MORONI, FLAVIO;CHIARUGI, ALBERTO
2009

Abstract

Upon massive DNA damage, hyperactivation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP)-1 causes severe depletion of intracellular NAD and ATP pools as well as mitochondrial dysfunction. Thus far, the molecular mechanisms contributing to PARP-1-dependent impairment of mitochondrial functioning have not been identified. We found that degradation of the PARP-1 product poly(ADP-ribose) through the concerted actions of poly(ADP-ribose) glycohydrolase and NUDIX (nucleoside diphosphate-X) hydrolases leads to accumulation of AMP. The latter, in turn, inhibits the ADP/ATP translocator, prompting mitochondrial energy failure. For the first time, our findings identify NUDIX hydrolases as key enzymes involved in energy derangement during PARP-1 hyperactivity. Also, these data disclose unanticipated AMP-dependent impairment of mitochondrial exchange of adenine nucleotides, which can be of relevance to organelle functioning and disease pathogenesis.
284
17668
17679
L. Formentini; A. Macchiarulo; G. Cipriani; E. Camaioni; E. Rapizzi; R. Pellicciari; F. Moroni; A. Chiarugi
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2158/389547
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