Poly(ADP-ribose) Catabolism Triggers AMP-dependent Mitochondrial Energy Failure |
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| Authors: | Laura Formentini Antonio Macchiarulo Giulia Cipriani Emidio Camaioni Elena Rapizzi Roberto Pellicciari Flavio Moroni and Alberto Chiarugi |
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| Institution: | From the ‡Department of Preclinical and Clinical Pharmacology, University of Florence, 50139 Firenze, ;the §Department of Medicinal Chemistry and Drug Technology, University of Perugia, 06100 Perugia, and ;the ¶Department of Biochemical Sciences, University of Florence, 50139 Firenze, Italy |
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| 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. |
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