Dynamin-related protein 1 controls the migration and neuronal differentiation of subventricular zone-derived neural progenitor cells.
Dynamin-related protein 1 controls the migration and neuronal differentiation of subventricular zone-derived neural progenitor cells.
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DOI：
10.1038/srep15962
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发表时间：
2015-10-30
影响因子：
4.6
通讯作者：
Sun W
中科院分区：
文献类型：
--
作者：
Kim HJ;Shaker MR;Cho B;Cho HM;Kim H;Kim JY;Sun W
线粒体在许多重要的细胞功能中都很重要，包括能量产生、钙稳态和细胞凋亡。这些细胞器分散在整个细胞质中，但它们的分布可根据局部能量需求而改变，比如细胞分裂和神经元成熟过程中。线粒体分布与线粒体分裂密切相关，阻断促进分裂的动力相关蛋白1（Drp1）的活性通常会导致线粒体伸长和聚集。在这项研究中，我们观察到线粒体优先定位于迁移的成年神经干细胞（aNSCs）的前沿突起，而神经元分化细胞则短暂地呈现线粒体在核周聚集。抑制Drp1活性会使典型的迁移细胞形态变为圆形，但线粒体的极化分布得以维持。随着这些变化，aNSCs无法迁移，神经元分化也被阻止。由于Drp1阻断也会损害线粒体膜电位，我们测试了补充左旋肉碱（一种可恢复线粒体膜电位和ATP合成的化合物）是否能够逆转由Drp1抑制所诱导的缺陷。有趣的是，左旋肉碱完全恢复了aNSC的缺陷，包括细胞皱缩、迁移以及受损的神经元分化。这些结果表明，Drp1是有功能活性的线粒体所必需的，并且补充ATP可以恢复由Drp1抑制所诱导的缺陷。
Mitochondria are important in many essential cellular functions, including energy production, calcium homeostasis, and apoptosis. The organelles are scattered throughout the cytoplasm, but their distribution can be altered in response to local energy demands, such as cell division and neuronal maturation. Mitochondrial distribution is closely associated with mitochondrial fission, and blocking the fission-promoting protein dynamin-related protein 1 (Drp1) activity often results in mitochondrial elongation and clustering. In this study, we observed that mitochondria were preferentially localized at the leading process of migratory adult neural stem cells (aNSCs), whereas neuronal differentiating cells transiently exhibited perinuclear condensation of mitochondria. Inhibiting Drp1 activity altered the typical migratory cell morphology into round shapes while the polarized mitochondrial distribution was maintained. With these changes, aNSCs failed to migrate, and neuronal differentiation was prevented. Because Drp1 blocking also impaired the mitochondrial membrane potential, we tested whether supplementing with L-carnitine, a compound that restores mitochondrial membrane potential and ATP synthesis, could revert the defects induced by Drp1 inhibition. Interestingly, L-carnitine fully restored the aNSC defects, including cell shrinkage, migration, and impaired neuronal differentiation. These results suggest that Drp1 is required for functionally active mitochondria, and supplementing with ATP can restore the defects induced by Drp1 suppression.