Dynamin-Related Protein 1 Deficiency Leads to Receptor-Interacting Protein Kinase 3-Mediated Necroptotic Neurodegeneration.
Dynamin-Related Protein 1 Deficiency Leads to Receptor-Interacting Protein Kinase 3-Mediated Necroptotic Neurodegeneration.
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DOI：
10.1016/j.ajpath.2016.06.025
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发表时间：
2016-11
期刊：
影响因子：
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通讯作者：
Tatsuya Yamada;Y. Adachi;M. Fukaya;M. Iijima;H. Sesaki
中科院分区：
文献类型：
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作者：
Tatsuya Yamada;Y. Adachi;M. Fukaya;M. Iijima;H. Sesaki
线粒体是动态细胞器，通过分裂和融合来调节其数量和形状。我们之前曾报道，介导线粒体分裂的动力相关蛋白1（Drp1）的缺失会导致小鼠小脑浦肯野细胞的变性。由于 Drp1 已被证明对细胞凋亡和坏死性凋亡很重要，因此浦肯野神经元在没有 Drp1 的情况下如何死亡令人费解。在这项研究中，我们通过生成浦肯野细胞特异性 Drp1 敲除 (KO) 小鼠来测试神经退行性疾病是否涉及坏死性细胞死亡，这些小鼠缺乏调节坏死性凋亡的受体相互作用蛋白激酶 3 (Rip3)。我们发现 Rip3 的缺失显着延缓了 Drp1-KO 浦肯野神经元的退化。此外，在神经变性之前，线粒体小管由于不受阻碍的融合而伸长，随后由于氧化损伤而变成大球体。令人惊讶的是，Rip3 的缺失还有助于 Drp1-KO 浦肯野细胞维持线粒体小管伸长的形态。这些数据表明，在线粒体分裂缺失的情况下，Rip3 在神经变性和线粒体形态学中发挥作用。
Mitochondria are dynamic organelles that divide and fuse to modulate their number and shape. We have previously reported that the loss of dynamin-related protein 1 (Drp1), which mediates mitochondrial division, leads to the degeneration of cerebellar Purkinje cells in mice. Because Drp1 has been shown to be important for apoptosis and necroptosis, it is puzzling how Purkinje neurons die in the absence of Drp1. In this study, we tested whether neurodegeneration involves necrotic cell death by generating Purkinje cell–specific Drp1-knockout (KO) mice that lack the receptor-interacting protein kinase 3 (Rip3), which regulates necroptosis. We found that the loss of Rip3 significantly delays the degeneration of Drp1-KO Purkinje neurons. In addition, before neurodegeneration, mitochondrial tubules elongate because of unopposed fusion and subsequently become large spheres as a result of oxidative damage. Surprisingly, Rip3 loss also helps Drp1-KO Purkinje cells maintain the elongated morphology of the mitochondrial tubules. These data suggest that Rip3 plays a role in neurodegeneration and mitochondrial morphology in the absence of mitochondrial division.