Mitochondrial and extramitochondrial apoptotic signaling pathways in cerebrocortical neurons
Mitochondrial and extramitochondrial apoptotic signaling pathways in cerebrocortical neurons
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DOI：
10.1073/pnas.100121097
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发表时间：
2000-05-23
影响因子：
11.1
通讯作者：
Lipton, SA
中科院分区：
文献类型：
--
作者：
Budd, SL;Tenneti, L;Lipton, SA
在培养的皮层神经元中，轻度兴奋性毒性损伤或星形孢菌素导致细胞凋亡，我们在这里表明，N-甲基-D-天冬氨酸（NMDA）受体介导的，但不是星形孢菌素介导的，细胞凋亡之前的线粒体膜电位（Δ psi m）和ATP的损失的去极化。然而，两种损伤都将细胞色素c（Cyt c）释放到细胞质中。是什么促使线粒体释放Cyt c以及释放的机制尚不清楚。我们研究了抑制腺嘌呤核苷酸转运子（ANT）的作用，ANT是线粒体通透性转换孔的一个假定成分。用米酵菌酸（BA）抑制线粒体ANT可阻止NMDA受体介导的皮层神经元凋亡。同时，BA阻止Δ psi m去极化，促进细胞ATP含量的恢复，并阻断caspase-3激活。然而，在BA存在下，Cyt c仍然被释放。由于BA阻止NMDA诱导的caspase-3激活和凋亡，在神经元细胞质中的Cyt c的存在是不足以诱导caspase活性或凋亡。与这些发现相反，BA在防止星形孢菌素诱导的半胱天冬酶激活或细胞凋亡方面是无效的。此外，星形孢菌素诱导的而非NMDA诱导的细胞凋亡与caspase-8的活化相关。这些结果表明，在大脑皮层培养，过度的NMDA受体激活沉淀神经元凋亡的线粒体功能障碍的手段，而星形孢菌素利用一个独特的途径。
In cultured cerebrocortical neurons, mild excitotoxic insults or staurosporine result in apoptosis, We show here that N-methyl-D-aspartate (NMDA) receptor-mediated, but not staurosporine-mediated, apoptosis is preceded by depolarization of the mitochondrial membrane potential (Delta psi m) and ATP loss. Both insults, however, release cytochrome c (Cyt c) into the cytoplasm. What prompts mitochondria to release Cyt c and the mechanism of release are as yet unknown. We examined the effect of inhibition of the adenine nucleotide translocator (ANT), a putative component of the mitochondrial permeability transition pore. Inhibition of the mitochondrial ANT with bongkrekic acid (BA) prevented NMDA receptor-mediated apoptosis of cerebrocortical neurons. Concomitantly, BA prevented Delta psi m depolarization, promoted recovery of cellular ATP content, and blocked caspase-3 activation. However, in the presence of BA, Cyt c was still released. Because BA prevented NMDA-induced caspase-3 activation and apoptosis, the presence of Cyt c in the neuronal cytoplasm is not sufficient for the induction of caspase activity or apoptosis. In contrast to these findings, BA was ineffective in preventing staurosporine-induced activation of caspases or apoptosis. Additionally, staurosporine-induced, but not NMDA-induced, apoptosis was associated with activation of caspase-8. These results indicate that, in cerebrocortical cultures, excessive NMDA receptor activation precipitates neuronal apoptosis by means of mitochondrial dysfunction, whereas staurosporine utilizes a distinct pathway.