Department of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Metallomics. 2017 Nov 15;9(11):1501-1512. doi: 10.1039/c7mt00221a.
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.
所有已知的真核生物的发育和生存都需要铜。铜的必要性反映了其广泛用作保守酶的辅助因子的用途，这些酶催化对能量产生、自由基解毒、胶原蛋白沉积、神经递质生物合成和铁稳态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，因为在未结合的形式下，铜可以增强自由基的产生并取代铁-硫簇，从而破坏蛋白质的功能。因此，进化出了保护机制来减轻这一挑战，并严格调节铜的获取、运输和储存，以使金属离子在细胞中很少以游离形式存在。过去十年中，许多研究小组的发现强调了这个监管框架是一个能够监测铜状态并在细胞和系统组织水平重新优先考虑铜使用的系统的基础。虽然相关分子机制和信号通路的鉴定被证明是困难的，并且仍然是我们全面理解铜稳态调节的一个障碍，但越来越多的证据表明，在线粒体作为一个关键枢纽，在健康和患病状态下都是如此。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其活性与其他细胞铜处理机制的活性相联系，以维持铜稳态。
