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。