ZnT9 function in the mitochondria

项目总结。 锌是许多生物过程的关键，包括基因表达和酶活性，然而，它是 高水平的有毒物质。细胞暴露在高水平的锌会导致酶活性的丧失，产生 活性氧簇(ROS)和细胞凋亡的激活。过量的锌对线粒体尤其有害， 由于它能够抑制电子转移链的几个组分。在许多细胞器中锌的浓度 是由转座子系统调节的；然而，这样的系统还没有在线粒体中显示出来。 利用生物信息学和细胞生物学检测相结合的方法，我们已经鉴定出了一种 候选线粒体转运体。这项提议的首要目标是检验这样一种假设，即锌是 线粒体锌的关键调节因子，在控制和病理条件下，其功能障碍可以 导致神经元损伤。我们提出，在正常情况下，线粒体质子梯度功率 锌从线粒体排出，限制锌毒性并提供神经保护功能。我们认为 线粒体的这种损伤被逆转，加速了损伤。这是锌的一种新功能 转运蛋白和一种新的神经保护机制以及神经毒性。为了测试这个模型，我们将 追求两个具体目标。本项目的目标1侧重于确定锌离子在 在正常情况下和受损的线粒体中，线粒体锌的流动。Aim 2将回答是否 在锌超载和氧化应激条件下，锌离子对细胞具有保护作用，以及锌离子是否发生逆转 加速神经细胞死亡。我们提议的研究可能会建立一个新的分子决定因素 线粒体锌转运和以前未知的锌神经毒性成分。完成 在这个探索性/发展研究计划中提出的研究可能会为 在活体小鼠模型中对锌锌转运蛋白9功能和功能障碍的未来研究和对锌转运蛋白9功能障碍的探索 这种转运蛋白可能与人类神经退行性疾病有关。

Project summary. Zinc is key to many of biological processes including gene expression and enzymatic activity, however, it is toxic at high levels. Exposure of cells to high levels of zinc leads to the loss of enzyme activity, generation of reactive oxygen species (ROS), and activation of apoptosis. Excess zinc is especially toxic to the mitochondria, due to its ability to inhibit several components of electron transfer chain. In many organelles zinc concentration is regulated by a system of transposers; however, such as system has not been shown for the mitochondria. Using a combination of bioinformatics and cell biological assays we have identified ZnT9 (SLC30A9) as a candidate mitochondrial transporter. The overarching goal of this proposal is to test the hypothesis that ZnT9 is a critical regulator of mitochondrial zinc under control and pathological conditions, and that its dysfunction can lead to neuronal injury. We propose that under normal conditions, the mitochondrial proton gradient powers zinc expulsion from the mitochondria, limiting zinc toxicity and providing a neuroprotection function. We think that in damages mitochondria ZnT9 is reversed, accelerating the damage. This is a novel function for a zinc transporter and a new mechanism of neuroprotection as well as neurotoxicity. To test this model, we will pursue two specific aims. Aim 1 of the present project is focused on identifying the role of ZnT9 in mitochondrial zinc fluxes under normal conditions and in damaged mitochondria. Aim 2 will answer whether ZnT9 is cytoprotective under zinc overload and oxidative stress conditions, and whether ZnT9 reversal accelerates neuronal cells death. Our proposed studies will likely establish a new molecular determinant of mitochondrial zinc transport and a previously unrecognized component of zinc neurotoxicity. The completion of the studies proposed in this Exploratory/Development Research Program will likely provide the rationale for future investigations of ZnT9 function and dysfunction in in vivo mouse models and an exploration of the possible link of this transporter to human neurodegenerative disorders.