The mitochondrion: a central architect of copper homeostasis.
The mitochondrion: a central architect of copper homeostasis.
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DOI：
10.1039/c7mt00221a
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发表时间：
2017-11-15
期刊：
影响因子：
--
通讯作者：
Leary SC
中科院分区：
文献类型：
--
作者：
Baker ZN;Cobine PA;Leary SC
所有已知的真核生物都需要铜才能发育和生存。铜的重要性反映了它在保守的酶中的广泛应用，这些保守的酶催化对能量产生、自由基解毒、胶原沉积、神经递质生物合成和铁的动态平衡至关重要的生化反应。然而，铜的优先使用给生物体带来了相当大的挑战，因为铜的非结合形式可以增强自由基的产生，并取代铁-硫簇来扰乱蛋白质的功能。因此，保护机制的发展缓解了这一挑战，并严格控制铜的获取、贩运和储存，使金属离子在细胞中很少以自由形式存在。多个组织在过去十年中的研究结果强调，这一监管框架构成了一个系统的基础，该系统能够监测铜的状态，并在组织的细胞和系统层面上重新确定铜使用的优先顺序。虽然相关的分子机制和信号通路的识别已经被证明是困难的，并且仍然是我们完全理解铜稳态调节的障碍，但越来越多的证据表明，在健康和疾病状态下，线粒体在这方面都是一个关键的枢纽。在这里，我们回顾了我们目前对细胞器内铜处理途径的理解，并考虑了一些可能的机制，这些机制可能有助于将它们的活性与其他细胞铜处理机制的活性相结合，以维持铜的动态平衡。
All known eukaryotes require copper for their development and survival. The essentiality of copper reflects its widespread use as a co-factor in conserved enzymes that catalyze biochemical reactions critical to energy production, free radical detoxification, collagen deposition, neurotransmitter biosynthesis and iron homeostasis. However, the prioritized use of copper poses an organism with a considerable challenge because, in its unbound form, copper can potentiate free radical production and displace iron-sulphur clusters to disrupt protein function. Protective mechanisms therefore evolved to mitigate this challenge and tightly regulate the acquisition, trafficking and storage of copper such that the metal ion is rarely found in its free form in the cell. Findings by a number of groups over the last ten years emphasize that this regulatory framework forms the foundation of a system that is capable of monitoring copper status and reprioritizing copper usage at both the cellular and systemic levels of organization. While the identification of relevant molecular mechanisms and signaling pathways has proven to be difficult and remains a barrier to our full understanding of the regulation of copper homeostasis, mounting evidence points to the mitochondrion as a pivotal hub in this regard in both healthy and diseased states. Here, we review our current understanding of copper handling pathways contained within the organelle and consider plausible mechanisms that may serve to functionally couple their activity to that of other cellular copper handling machinery to maintain copper homeostasis.
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