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Getting out what you put in: Copper in mitochondria and its impacts on human disease
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research ( IF 5.1 ) Pub Date : 2020-10-02 , DOI: 10.1016/j.bbamcr.2020.118867
Paul A Cobine 1 , Stanley A Moore 2 , Scot C Leary 2
Affiliation  

Mitochondria accumulate copper in their matrix for the eventual maturation of the cuproenzymes cytochrome c oxidase and superoxide dismutase. Transport into the matrix is achieved by mitochondrial carrier family (MCF) proteins. The major copper transporting MCF described to date in yeast is Pic2, which imports the metal ion into the matrix. Pic2 is one of ~30 MCFs that move numerous metabolites, nucleotides and co-factors across the inner membrane for use in the matrix. Genetic and biochemical experiments showed that Pic2 is required for cytochrome c oxidase activity under copper stress, and that it is capable of transporting ionic and complexed forms of copper. The Pic2 ortholog SLC25A3, one of 53 mammalian MCFs, functions as both a copper and a phosphate transporter. Depletion of SLC25A3 results in decreased accumulation of copper in the matrix, a cytochrome c oxidase defect and a modulation of cytosolic superoxide dismutase abundance. The regulatory roles for copper and cuproproteins resident to the mitochondrion continue to expand beyond the organelle. Mitochondrial copper chaperones have been linked to the modulation of cellular copper uptake and export and the facilitation of inter-organ communication. Recently, a role for matrix copper has also been proposed in a novel cell death pathway termed cuproptosis. This review will detail our understanding of the maturation of mitochondrial copper enzymes, the roles of mitochondrial signals in regulating cellular copper content, the proposed mechanisms of copper transport into the organelle and explore the evolutionary origins of copper homeostasis pathways.



中文翻译:

取出你投入的东西:线粒体中的铜及其对人类疾病的影响

线粒体在其基质中积累铜,用于铜酶细胞色素c氧化酶和超氧化物歧化酶的最终成熟。转运到基质中是通过线粒体载体家族 (MCF) 蛋白实现的。迄今为止在酵母中描述的主要铜转运 MCF 是 Pic2,它将金属离子导入到基质中。Pic2 是约 30 个 MCF 之一,可将众多代谢物、核苷酸和辅因子移动穿过内膜以用于基质。遗传和生化实验表明,Pic2 是细胞色素c所必需的铜胁迫下的氧化酶活性,并且它能够运输离子和络合形式的铜。Pic2 直向同源物 SLC25A3 是 53 种哺乳动物 MCF 之一,同时具有铜和磷酸盐转运蛋白的功能。SLC25A3 的消耗导致基质中铜的积累减少,这是一种细胞色素c氧化酶缺陷和细胞溶质超氧化物歧化酶丰度的调节。驻留在线粒体中的铜和铜蛋白的调节作用继续扩展到细胞器之外。线粒体铜伴侣蛋白与细胞铜摄取和输出的调节以及器官间通讯的促进有关。最近,还提出了基质铜在称为细胞凋亡的新型细胞死亡途径中的作用。这篇综述将详细介绍我们对线粒体铜酶成熟的理解、线粒体信号在调节细胞铜含量中的作用、铜转运到细胞器中的拟议机制,并探索铜稳态途径的进化起源。

更新日期:2020-10-02
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