Poly(ADP-ribose) Catabolism Triggers AMP-dependent Mitochondrial Energy Failure

被引:82
作者
Formentini, Laura
Macchiarulo, Antonio [2 ]
Cipriani, Giulia
Camaioni, Emidio [2 ]
Rapizzi, Elena [3 ]
Pellicciari, Roberto [2 ]
Moroni, Flavio [1 ]
Chiarugi, Alberto [1 ]
机构
[1] Univ Florence, Dept Preclin & Clin Pharmacol, I-50139 Florence, Italy
[2] Univ Perugia, Dept Med Chem & Drug Technol, I-06100 Perugia, Italy
[3] Univ Florence, Dept Biochem Sci, I-50139 Florence, Italy
关键词
APOPTOSIS-INDUCING FACTOR; INDUCED CELL-DEATH; ADP/ATP CARRIER; PAR POLYMER; ADP-RIBOSE; GLYCOHYDROLASE; NUCLEAR; NAD(+); METABOLISM; INHIBITORS;
D O I
10.1074/jbc.M109.002931
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:17668 / 17676
页数:9
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