Deadly conversations: Nuclear-mitochondrial cross-talk
Deadly conversations: Nuclear-mitochondrial cross-talk
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DOI：
10.1023/b:jobb.0000041755.22613.8d
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发表时间：
2004-08-01
影响因子：
3
通讯作者：
Dawson, TM
中科院分区：
文献类型：
--
作者：
Dawson, VL;Dawson, TM
中风或神经退行性疾病后的神经元损伤被认为部分源于谷氨酸对N-甲基-D-天冬氨酸（NMDA）受体的过度兴奋。NMDA受体引发的神经毒性在很大程度上是通过激活神经元型一氧化氮合酶（nNOS）和产生一氧化氮（NO）介导的。线粒体中超氧阴离子的同时产生为过氧亚硝酸根（ONOO-）的形成提供了容许环境。过氧亚硝酸盐损伤DNA，导致链断裂和聚（ADP-核糖）聚合酶-1（PARP-1）活化。这种信号级联在NMDA兴奋性毒性以及中风和帕金森病的实验模型中起关键作用。PARP-1介导的神经元死亡的机制刚刚被揭示。虽然在PARP激活后很容易观察到ATP和NAD的减少，但尚不清楚ATP和NAD的损失是否有助于神经元死亡级联反应或仅仅是PARP-1激活的生化标志物。凋亡诱导因子（AIF）通常定位于线粒体，但在PARP-1激活后，AIF易位至细胞核，引发染色质凝聚、DNA片段化和核收缩。此外，磷脂酰丝氨酸被暴露，在稍后的时间点细胞色素c被释放，半胱天冬酶-3被激活。在兴奋毒性神经元死亡的情况下，AIF毒性是半胱天冬酶独立的。这些观察结果与神经元损伤模型中细胞凋亡的生物化学特征的报告一致，但半胱天冬酶抑制剂的保护作用不大。AIF很可能是形态学和生化事件的效应子，并且是神经元细胞死亡的承诺点，这些事件发生在半胱天冬酶激活之前，因此解释了半胱天冬酶抑制剂的有限作用。细胞核和线粒体之间存在显著的串扰，最终导致神经元细胞死亡。在利用该途径开发新疗法时，重要的是阻断AIF从线粒体易位到细胞核，而不损害线粒体中AIF的重要生理功能。
Neuronal damage following stroke or neurodegenerative diseases is thought to stem in part from overexcitation of N-methyl-D-aspartate ( NMDA) receptors by glutamate. NMDA receptors triggered neurotoxicity is mediated in large part by activation of neuronal nitric oxide synthase (nNOS) and production of nitric oxide (NO). Simultaneous production of superoxide anion in mitochondria provides a permissive environment for the formation of peroxynitrite (ONOO-). Peroxynitrite damages DNA leading to strand breaks and activation of poly(ADP-ribose) polymerase-1 (PARP-1). This signal cascade plays a key role in NMDA excitotoxicity, and experimental models of stroke and Parkinson's disease. The mechanisms of PARP-1-mediated neuronal death are just being revealed. While decrements in ATP and NAD are readily observed following PARP activation, it is not yet clear whether loss of ATP and NAD contribute to the neuronal death cascade or are simply a biochemical marker for PARP-1 activation. Apoptosis-inducing factor (AIF) is normally localized to mitochondria but following PARP-1 activation, AIF translocates to the nucleus triggering chromatin condensation, DNA fragmentation and nuclear shrinkage. Additionally, phosphatidylserine is exposed and at a later time point cytochrome c is released and caspase-3 is activated. In the setting of excitotoxic neuronal death, AIF toxicity is caspase independent. These observations are consistent with reports of biochemical features of apoptosis in neuronal injury models but modest to no protection by caspase inhibitors. It is likely that AIF is the effector of the morphologic and biochemical events and is the commitment point to neuronal cell death, events that occur prior to caspase activation, thus accounting for the limited effects of caspase inhibitors. There exists significant cross talk between the nucleus and mitochondria, ultimately resulting in neuronal cell death. In exploiting this pathway for the development of new therapeutics, it will be important to block AIF translocation from the mitochondria to the nucleus without impairing important physiological functions of AIF in the mitochondria.