Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice
Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice
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DOI：
10.1101/gad.1779509
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发表时间：
2009-05-15
影响因子：
10.5
通讯作者：
Tsai, Ting-Fen
中科院分区：
文献类型：
--
作者：
Chen, Yi-Fan;Kao, Cheng-Heng;Tsai, Ting-Fen
CISD 2是Wolfram综合征2型（WFS 2）的致病基因，是一个尚未被鉴定的新基因。值得注意的是，CISD 2基因位于人类染色体4 q上，那里是长寿的遗传组成部分。在这里，我们首次表明，CISD 2参与哺乳动物的寿命控制。小鼠中的cisd 2缺乏导致线粒体破裂和功能障碍，伴随着自噬性细胞死亡，这些事件先于神经和肌肉变性的两种最早表现;它们一起导致一组表型特征，提示过早衰老。我们的研究还表明，Cisd 2主要定位于线粒体中，并且线粒体变性似乎具有直接的表型后果，其触发Cisd 2敲除小鼠的加速衰老过程;此外，线粒体变性随着年龄的增长而加剧，自噬增加与早衰表型的发展平行。此外，我们的Cisd 2敲除小鼠工作提供了强有力的证据支持早期的临床假设，即WFS在一定程度上是线粒体介导的疾病;具体来说，我们提出CISD 2的突变导致人类线粒体介导的疾病WFS 2。因此，这种突变小鼠提供了一种动物模型，用于研究Cisd 2蛋白功能的机制，并有助于理解WFS 2的病理生理学。
CISD2, the causative gene for Wolfram syndrome 2 (WFS2), is a previously uncharacterized novel gene. Significantly, the CISD2 gene is located on human chromosome 4q, where a genetic component for longevity maps. Here we show for the first time that CISD2 is involved in mammalian life-span control. Cisd2 deficiency in mice causes mitochondrial breakdown and dysfunction accompanied by autophagic cell death, and these events precede the two earliest manifestations of nerve and muscle degeneration; together, they lead to a panel of phenotypic features suggestive of premature aging. Our study also reveals that Cisd2 is primarily localized in the mitochondria and that mitochondrial degeneration appears to have a direct phenotypic consequence that triggers the accelerated aging process in Cisd2 knockout mice; furthermore, mitochondrial degeneration exacerbates with age, and the autophagy increases in parallel to the development of the premature aging phenotype. Additionally, our Cisd2 knockout mouse work provides strong evidence supporting an earlier clinical hypothesis that WFS is in part a mitochondria-mediated disorder; specifically, we propose that mutation of CISD2 causes the mitochondria-mediated disorder WFS2 in humans. Thus, this mutant mouse provides an animal model for mechanistic investigation of Cisd2 protein function and help with a pathophysiological understanding of WFS2.