Copper Transport by Members of the Mitochondrial Carrier Family

铜是人类生存和正常发育的关键元素，但它对细胞也有毒性 如果处理不当。事实上，即使是轻微的铜稳态破坏也会导致一系列疾病 包括糖尿病、心血管疾病、阿尔茨海默病、肌萎缩侧索硬化症和帕金森病 疾病对铜的需求部分是由于它在末端电子传递中作为辅因子的作用 链复合细胞色素c氧化酶。虽然铜在线粒体功能中起着重要作用， 关于它如何被募集到细胞器并在细胞器内分布的知识非常有限。假设是 在这里测试的是线粒体载体家族蛋白，用于跨膜转运底物， 内膜对铜稳态至关重要。所提出的目的和实验联合收割机在体内和 体外分析铜依赖性表型和转运测定以确定线粒体 载体家族蛋白在铜转运中的作用我们将证明这种蛋白质的铜转运功能， 细胞培养和动物模型，通过评估铜依赖性酶的丰度和活性， 线粒体中的铜和全细胞中的总铜。数据来自于 这些目标将导致我们对线粒体铜稳态的理解取得重大进展， 人类这一提议的影响是，通过鉴定线粒体铜转运蛋白获得的知识 不仅有助于我们理解基础生物学， 处理不当或线粒体功能障碍。这些疾病中有许多目前无法治愈， 将为治疗干预提供潜在的药物靶点。

Copper is a key element in the survival and normal development of humans but it is also toxic to cells when mishandled. In fact even mild disruption of copper homeostasis causes a wide array of disorders including diabetes, cardiovascular disease, Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease. The requirement for copper is in part due to its role as a cofactor in the terminal electron transport chain complex cytochrome c oxidase. Though copper has an essential role in mitochondrial function, our knowledge of how it is recruited to, and distributed within, the organelle is very limited. The hypothesis to be tested here is that mitochondrial carrier family proteins that are used for translocation of substrates across the inner membrane are critical to copper homeostasis. The proposed aims and experiments combine in vivo and in vitro analysis of copper dependent phenotypes and transport assays to establish a role for a mitochondrial carrier family protein in copper transport. We will demonstrate the copper transport function of this protein in cell culture and an animal model by assessing the abundance and activity of copper-dependent enzymes, total copper in mitochondria and total copper in whole cells. Data generated from the experiments proposed in these aims will result in significant advances in our understanding of mitochondrial copper homeostasis in humans. The impact of this proposal is that knowledge gained by identifying a mitochondrial copper transporter can contribute to our understanding basic biology but also to a wide spectrum of diseases caused by copper mishandling or mitochondrial dysfunction. Many of these diseases are currently untreatable and this proposal will provide a potential druggable target for therapeutic intervention.