Poly(ADP-ribose) Catabolism Triggers AMP-dependent Mitochondrial Energy Failure
Poly(ADP-ribose) Catabolism Triggers AMP-dependent Mitochondrial Energy Failure
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DOI：
10.1074/jbc.m109.002931
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发表时间：
2009-06-26
影响因子：
4.8
通讯作者：
Chiarugi, Alberto
中科院分区：
文献类型：
--
作者：
Formentini, Laura;Macchiarulo, Antonio;Chiarugi, Alberto
当DNA大量损伤时，核酶多聚(ADP-核糖)聚合酶(PARP)-1的过度激活会导致细胞内NAD和ATP池的严重耗尽以及线粒体功能障碍。到目前为止，PARP-1依赖的线粒体功能损伤的分子机制尚未确定。我们发现，PARP-1产物聚ADP-核糖通过聚ADP-核糖水解酶和NUDIX(核苷二磷酸-X)水解酶的协同作用而降解，导致AMP的积累。后者反过来抑制ADP/ATP转运体，促使线粒体能量衰竭。我们的发现首次将NUDIX水解酶确定为参与PARP-1过度活动过程中能量紊乱的关键酶。此外，这些数据揭示了腺嘌呤核苷酸线粒体交换的意外损害，这可能与细胞器功能和疾病发病机制有关。
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.