Nitric oxide-induced cell death in developing oligodendrocytes is associated with mitochondrial dysfunction and apoptosis-inducing factor translocation
Nitric oxide-induced cell death in developing oligodendrocytes is associated with mitochondrial dysfunction and apoptosis-inducing factor translocation
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DOI：
10.1111/j.1460-9568.2004.03616.x
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发表时间：
2004-10-01
影响因子：
3.4
通讯作者：
Rosenberg, PA
中科院分区：
文献类型：
--
作者：
Baud, O;Li, JR;Rosenberg, PA
活性氮物质被认为参与了缺氧缺血性和尼古丁诱导的脑损伤，包括室周白质软化（PVL），早产儿脑瘫的主要病理基质。PVL似乎是围产期炎症事件和脑白色物质缺氧缺血性损伤的结果。PVL引起的慢性髓鞘形成障碍表明发育中的少突胶质细胞（OLs）参与其发病机制。我们假设一氧化氮（NO）可能通过对发育中的OLs的毒性作用参与PVL的发病机制。使用高度富集的OL的原代培养物，我们发现NO对发育中的OL（O 4（+），O 1（-），MBP-）是有毒的，DETANONOATE的EC 50值为236 +/- 125 mum。过氧亚硝酸盐的形成似乎并不涉及NO毒性在发展中的OL，确定的过氧亚硝酸盐清除剂以及超氧化物歧化酶过度表达，以防止NO诱导的毒性失败。同样，涉及PARP、兴奋性毒性、鸟苷酸环化酶和半胱天冬酶激活的几种途径与NO对发育中OL的毒性无关。NO对OL的毒性导致发育中OL的ATP耗竭和线粒体膜电位（DeltaPsi）损失。凋亡诱导因子（AIF）已被证明是参与半胱天冬酶非依赖性细胞死亡，我们发现，AIF易位从线粒体到细胞核后，NO暴露。总之，我们认为，发展中的OL的脆弱性，NO涉及线粒体功能障碍和易位的AIF从线粒体到细胞核。
Reactive nitrogen species are thought to be involved in both hypoxic-ischemic and cytokine-induced brain injury, including periventricular leukomalacia (PVL), the major pathological substrate of cerebral palsy in premature infants. PVL appears to be the result of perinatal inflammatory events and hypoxic-ischemic injury to the cerebral white matter. The chronic disturbance of myelination resulting from PVL suggests that developing oligodendrocytes (OLs) are involved in its pathogenesis. We hypothesized that nitric oxide (NO) could participate in the pathogenesis of PVL through a toxic effect on developing OLs. Using primary cultures of highly enriched OLs we found that NO is toxic to developing OLs (O4(+), O1(-), MBP-), with an EC50 value of 236 +/- 125 mum of DETANOnoate. Peroxynitrite formation does not appear to be involved in NO toxicity in developing OLs, as determined by the failure of peroxynitrite scavengers as well as superoxide dismutase overexpression to prevent NO-induced toxicity. Similarly, several pathways involving PARP, excitotoxicity, guanylyl cyclase and caspase activation were not related to NO toxicity to developing OLs. NO toxicity to OLs resulted in ATP depletion and loss of mitochondrial membrane potential (DeltaPsi) in developing OLs. Apoptosis-inducing factor (AIF) has been shown to be involved in caspase-independent cell death, and we found that AIF translocated from mitochondria into the nucleus upon NO exposure. In conclusion, we suggest that the vulnerability of developing OLs to NO involves mitochondrial dysfunction and translocation of AIF from mitochondria to nuclei.