ZnT9 function in the mitochondria

ZnT9 在线粒体中的功能

• 批准号: 9763914
• 负责人: Elias Aizenman
• 金额: $ 43.18万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763914
• 关键词: Apoptosis; Automobile Driving; Binding Proteins; Bioinformatics; Biological Assay; Biological Process; Cell Death; Cell Death Signaling Process; Cells; Complex; Electron Transport; Elements; Functional disorder; Future; Gene Expression; Generations; Genetic Transcription; Goals; Hela Cells; Human; Impairment; Inner mitochondrial membrane; Investigation; Lead; Left; Link; Metallothionein; Metals; Mitochondria; Mitochondrial Matrix; Modeling; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Injury; Neurons; Organelles; Oxidative Stress; Oxygen; Pathologic; Phosphorylation; Process; Protons; Reactive Oxygen Species; Regulation; Role; Signal Transduction; Stroke; System; Testing; Toxic effect; Traumatic Brain Injury; VDAC1 gene; Zinc; antiporter; base; cell injury; cytotoxic; enzyme activity; excitotoxicity; in vivo; knock-down; mitochondrial dysfunction; mouse model; neuron loss; neuroprotection; neurotoxicity; novel; operation; overexpression; programs; research and development; response; uptake; zinc-binding protein

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.

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 高浓度有毒。细胞暴露于高浓度的锌会导致酶活性丧失，产生 活性氧（ROS）和细胞凋亡的激活。过量的锌对线粒体尤其有毒， 由于它能够抑制电子传递链的多个组成部分。许多细胞器中的锌浓度 由转位器系统调节；然而，这样的系统尚未在线粒体中得到证实。 结合生物信息学和细胞生物学测定，我们已将 ZnT9 (SLC30A9) 确定为 候选线粒体转运蛋白。该提案的总体目标是检验 ZnT9 的假设 在控制和病理条件下线粒体锌的关键调节因子，其功能障碍可以 导致神经元损伤。我们建议在正常条件下，线粒体质子梯度功率 锌从线粒体中排出，限制锌毒性并提供神经保护功能。我们认为 线粒体损伤中的 ZnT9 发生逆转，加速了损伤。这是锌的一个新功能 转运蛋白和神经保护和神经毒性的新机制。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 重点是确定 ZnT9 在 正常条件下和受损线粒体中的线粒体锌通量。目标 2 将回答是否 ZnT9 在锌超载和氧化应激条件下具有细胞保护作用，以及 ZnT9 是否逆转 加速神经细胞死亡。我们提出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被识别的锌神经毒性成分。完成 本探索性/发展研究计划中提出的研究可能会提供以下理由： 体内小鼠模型中 ZnT9 功能和功能障碍的未来研究以及对 ZnT9 功能和功能障碍的探索 该转运蛋白与人类神经退行性疾病可能存在联系。