Promotion of mitochondrial biogenesis by necdin protects neurons against mitochondrial insults.
Promotion of mitochondrial biogenesis by necdin protects neurons against mitochondrial insults.
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DOI：
10.1038/ncomms10943
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发表时间：
2016-03-14
影响因子：
16.6
通讯作者：
Yoshikawa K
中科院分区：
文献类型：
--
作者：
Hasegawa K;Yasuda T;Shiraishi C;Fujiwara K;Przedborski S;Mochizuki H;Yoshikawa K
神经元的功能和生存严重依赖线粒体。线粒体功能障碍有助于神经退行性疾病如帕金森病的发病机制。PGC-1α是线粒体生物发生和功能的主要调节因子。在这里，我们确定necdin作为一个有效的PGC-1α稳定剂，促进线粒体生物合成通过PGC-1α在哺乳动物神经元。在necdin缺失的皮质神经元中，编码PGC-1α特异性蛋白的基因的表达显著降低，其中线粒体功能和PGC-1α蛋白的表达降低。Necdin通过抑制PGC-1α的泛素依赖性降解而强烈稳定PGC-1α。necdin的强制表达增强了原代皮层神经元和人SH-SY 5 Y神经母细胞瘤细胞中的线粒体功能，以防止线粒体呼吸链激酶诱导的变性。此外，necdin在成年小鼠体内黑质中的过表达保护多巴胺能神经元免受实验性帕金森病的变性。这些数据表明，necdin通过稳定内源性PGC-1α来促进线粒体生物合成，从而对线粒体损伤发挥神经保护作用。 线粒体功能障碍发生在帕金森氏病，虽然潜在的机制尚不清楚。在这里，作者发现necdin可以稳定线粒体调节因子PGC-1α，并且necdin的过表达可以在体外和体内保护MPTP介导的神经变性。
Neurons rely heavily on mitochondria for their function and survival. Mitochondrial dysfunction contributes to the pathogenesis of neurodegenerative diseases such as Parkinson's disease. PGC-1α is a master regulator of mitochondrial biogenesis and function. Here we identify necdin as a potent PGC-1α stabilizer that promotes mitochondrial biogenesis via PGC-1α in mammalian neurons. Expression of genes encoding mitochondria-specific proteins decreases significantly in necdin-null cortical neurons, where mitochondrial function and expression of the PGC-1α protein are reduced. Necdin strongly stabilizes PGC-1α by inhibiting its ubiquitin-dependent degradation. Forced expression of necdin enhances mitochondrial function in primary cortical neurons and human SH-SY5Y neuroblastoma cells to prevent mitochondrial respiratory chain inhibitor-induced degeneration. Moreover, overexpression of necdin in the substantia nigra in vivo of adult mice protects dopaminergic neurons against degeneration in experimental Parkinson's disease. These data reveal that necdin promotes mitochondrial biogenesis through stabilization of endogenous PGC-1α to exert neuroprotection against mitochondrial insults. Mitochondrial dysfunction occurs in Parkinson's disease, although the underlying mechanisms are unclear. Here, the authors find necdin works to stabilise the mitochondrial regulator PGC-1α, and that overexpression of necdin protects against MPTP-mediated neurodegeneration both in vitro and in vivo.