Nitration of the mitochondrial complex I subunit NDUFB8 elicits RIP1- and RIP3-mediated necrosis.
Nitration of the mitochondrial complex I subunit NDUFB8 elicits RIP1- and RIP3-mediated necrosis.
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DOI：
10.1016/j.freeradbiomed.2009.11.001
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发表时间：
2010-01-15
影响因子：
7.4
通讯作者：
Madesh, Muniswamy
中科院分区：
文献类型：
--
作者：
Davis, Christiana W.;Hawkins, Brian J.;Ramasamy, Subbiah;Irrinki, Krishna M.;Cameron, Bruce A.;Islam, Khalid;Daswani, Varsha P.;Doonan, Patrick J.;Manevich, Yefim;Madesh, Muniswamy
一氧化氮和其他活性氮物质靶向线粒体中的多个位点，以影响细胞生物能量学和存活。动力学成像研究表明，无论是活化的巨噬细胞或供体化合物的NO迅速扩散到线粒体，导致剂量依赖性的渐进增加NO依赖性的线粒体膜电位的损失，并开始改变细胞的生物能量，最终导致坏死性细胞死亡。细胞功能障碍由线粒体复合物I亚基NDUFB 8的升高的3-硝基酪氨酸特征介导，其对于正常线粒体功能至关重要，如通过siRNA的选择性敲低所证明的。线粒体超氧化物歧化酶的过表达大大降低NDUFB 8硝化和恢复线粒体的稳态。此外，用necrostatin-1或siRNA敲低RIP 1和RIP 3处理细胞可防止NO介导的坏死。这项工作表明，NO和神经源性超氧化物之间的相互作用改变线粒体生物能量学和细胞功能，从而提供了活性氧和氮物种介导的线粒体稳态改变的分子机制。
Nitric oxide and other reactive nitrogen species target multiple sites in the mitochondria to impact cellular bioenergetics and survival. Kinetic imaging studies revealed that NO from either activated macrophages or donor compounds rapidly diffuses to the mitochondria, causing a dose dependent progressive increase in NO-dependent DAF fluorescence that corresponded to mitochondrial membrane potential loss, and initiated alterations in cellular bioenergetics that ultimately led to necrotic cell death. Cellular dysfunction is mediated by an elevated 3-nitrotyrosine signature of the mitochondrial complex I subunit NDUFB8, which is vital for normal mitochondrial function as evidenced by selective knockdown via siRNA. Overexpression of mitochondrial superoxide dismutase substantially decreased NDUFB8 nitration and restored mitochondrial homeostasis. Further, treatment of cells with either necrostatin-1 or siRNA knockdown of RIP1 and RIP3 prevented NO-mediated necrosis. This work demonstrates that the interaction between NO and mitochondrially-derived superoxide alters mitochondrial bioenergetics and cell function, thus providing a molecular mechanism for reactive oxygen and nitrogen species-mediated alterations in mitochondrial homeostasis.
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