NAD+ as a metabolic link between DNA damage and cell death
NAD+ as a metabolic link between DNA damage and cell death
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DOI：
10.1002/jnr.20289
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发表时间：
2005-01-01
影响因子：
4.2
通讯作者：
Swanson, RA
中科院分区：
文献类型：
--
作者：
Ying, WH;Alano, CC;Swanson, RA
DNA损伤发生在缺血、兴奋毒性、炎症和其他影响中枢神经系统（CNS）的疾病中。广泛的DNA损伤触发细胞死亡，在成熟的中枢神经系统中，这主要是通过激活聚（adp -核糖）聚合酶-1 （PARP-1）细胞死亡途径发生的。PARP-1是一种丰富的核酶，当DNA损伤激活时，它消耗烟酰胺腺嘌呤二核苷酸（NAD）（+）在受体蛋白上形成聚（adp -核糖）。PARP-1激活导致细胞死亡的机制尚不完全清楚。我们使用小鼠星形胶质细胞培养来探索PARP-1消耗NAD（+）的生物能量效应以及NAD（+）消耗在这种细胞死亡程序中的作用。以葡萄糖为唯一外源能量底物的DNA烷基化剂n -甲基-n′-硝基-n -亚硝基胍（MNNG）诱导PARP-1活化。PARP-1激活导致星形胶质细胞NAD（+）快速但不完全消耗，糖酵解几乎完全阻断，最终导致细胞死亡。细胞内NAD（+）的充满恢复糖酵解功能并防止细胞死亡。在培养基中加入非葡萄糖底物，如丙酮酸、谷氨酸或谷氨酰胺，也可以防止PARP-1激活后星形胶质细胞死亡。这些研究表明，PARP-1的激活导致细胞质的快速耗竭，而不是线粒体NAD（+）库的耗竭。胞质内NAD（+）池的耗竭使细胞不能利用葡萄糖作为代谢底物。在葡萄糖是唯一可用的代谢底物的条件下，这会导致细胞死亡。这种细胞死亡途径与大脑特别相关，因为葡萄糖通常是唯一快速通过血脑屏障运输的代谢底物。(C) 2004 Wiley-Liss, Inc。
DNA damage occurs in ischemia, excitotoxicity, inflammation, and other disorders that affect the central nervous system (CNS). Extensive DNA damage triggers cell death and in the mature CNS, this occurs primarily through activation of the poly(ADP-ribose) polymerase-1 (PARP-1) cell death pathway. PARP-1 is an abundant nuclear enzyme that, when activated by DNA damage, consumes nicotinamide adenine dinucleotide (NAD)(+) to form poly(ADP-ribose) on acceptor proteins. The mechanisms by which PARP-1 activation leads to cell death are not understood fully. We used mouse astrocyte cultures to explore the bioenergetic effects of NAD(+) depletion by PARP-1 and the role of NAD(+) depletion in this cell death program. PARP-1 activation was induced by the DNA alkylating agent, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), using medium in which glucose was the only exogenous energy substrate. PARP-1 activation led to a rapid but incomplete depletion of astrocyte NAD(+), a near-complete block in glycolysis, and eventual cell death. Repletion of intracellular NAD(+) restored glycolytic function and prevented cell death. The addition of non-glucose substrates to the medium, pyruvate, glutamate, or glutamine, also prevented astrocyte death after PARP-1 activation. These studies suggest PARP-1 activation leads to rapid depletion of the cytosolic but not the mitochondrial NAD(+) pool. Depletion of the cytosolic NAD(+) pool renders the cells unable to utilize glucose as a metabolic substrate. Under conditions where glucose is the only available metabolic substrate, this leads to cell death. This cell death pathway is particularly germane to brain because glucose is normally the only metabolic substrate that is transported rapidly across the blood-brain barrier. (C) 2004 Wiley-Liss, Inc.