SLC-30A9 is required for Zn2+ homeostasis, Zn2+ mobilization, and mitochondrial health
SLC-30A9 is required for Zn2+ homeostasis, Zn2+ mobilization, and mitochondrial health
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SLC-30A9 是 Zn2 稳态、Zn2 动员和线粒体健康所必需的
DOI：
10.1073/pnas.2023909118
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发表时间：
2021-08-25
影响因子：
11.1
通讯作者：
Wang, Xiangming
中科院分区：
文献类型：
--
作者：
Deng, Huichao;Qiao, Xinhua;Wang, Xiangming
微量元素锌对生理学的许多方面都至关重要。线粒体是主要的锌离子（Zn²⁺）储存库，线粒体中过量的锌离子与神经退行性变有关。线粒体如何维持其锌离子稳态尚不清楚。在此，我们发现SLC - 30A9转运蛋白定位于线粒体上，并且在秀丽隐杆线虫和人类细胞中都是线粒体输出锌离子所必需的。slc - 30a9的缺失导致线粒体中锌离子水平升高，许多组织中的线粒体基质严重肿胀，线粒体代谢功能受损，还原性应激以及线粒体应激反应的诱导。在秀丽隐杆线虫中，SLC - 30A9对生物体的生育能力和精子激活也是必不可少的，在此过程中锌离子从线粒体中排出并作为一种激活信号。在slc - 30a9缺陷型神经元中，畸形的线粒体在轴突和树突中的分布减少，这为发现SLC30A9突变的伯克 - 兰道 - 佩雷斯脑肾综合征提供了一种潜在的机制。
Significance Zinc plays important roles in numerous cellular processes. Deficiency or excess of Zn2+ leads to many diseases. Zn2+ concentration at various cellular compartments is regulated. Imbalance of Zn2+ in mitochondria has been linked to neurodegeneration. However, little is known about how mitochondrial Zn2+ is regulated. We find that SLC-30A9 is required for Zn2+ export from mitochondria in both Caenorhabditis elegans and human cells. Loss of slc-30a9 leads to excessive Zn2+ accumulation in mitochondria, severe mitochondrial swelling, compromised mitochondrial metabolic function, reductive stress, and induction of the mitochondrial stress response. SLC-30A9 is also essential for organismal fertility and sperm activation. In neurons, slc-30a9 mutations cause dramatically reduced mitochondria in neurites, providing a potential mechanism for the Birk–Landau–Perez cerebrorenal syndrome. The trace element zinc is essential for many aspects of physiology. The mitochondrion is a major Zn2+ store, and excessive mitochondrial Zn2+ is linked to neurodegeneration. How mitochondria maintain their Zn2+ homeostasis is unknown. Here, we find that the SLC-30A9 transporter localizes on mitochondria and is required for export of Zn2+ from mitochondria in both Caenorhabditis elegans and human cells. Loss of slc-30a9 leads to elevated Zn2+ levels in mitochondria, a severely swollen mitochondrial matrix in many tissues, compromised mitochondrial metabolic function, reductive stress, and induction of the mitochondrial stress response. SLC-30A9 is also essential for organismal fertility and sperm activation in C. elegans, during which Zn2+ exits from mitochondria and acts as an activation signal. In slc-30a9–deficient neurons, misshapen mitochondria show reduced distribution in axons and dendrites, providing a potential mechanism for the Birk–Landau–Perez cerebrorenal syndrome where an SLC30A9 mutation was found.