Prime Real Estate: Metals, Cofactors and MICOS.
Prime Real Estate: Metals, Cofactors and MICOS.
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DOI：
10.3389/fcell.2022.892325
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发表时间：
2022
影响因子：
5.5
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中科院分区：
文献类型：
--
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金属是人类生存和正常发育的关键元素，但如果处理不当，也可能对细胞有毒。事实上，即使是轻微的金属体内平衡的破坏也会引起一系列的疾病。许多正常生理所必需的金属是线粒体中酶活动和必要辅因子形成所必需的。铜是终端电子传递链复合体细胞色素c氧化酶的辅助因子，铁是铁硫（Fe-S）簇和血红素形成所必需的，锰是防止氧化应激产生所必需的，这些只是线粒体金属发挥关键作用的几个例子。尽管这些金属的靶标是已知的，但我们仍在识别转运蛋白，研究已知转运蛋白的作用，并确定转运过程的调节因子。线粒体是一种动态细胞器，其含量、结构和在细胞内的定位在不同的组织和生物体中是不同的。我们对线粒体生理变化对这些细胞器中金属含量和利用的影响的了解非常有限。裂变和融合的速率、细胞器的超微结构和有丝自噬的速率都能影响金属稳态和辅助因子的组装。本文将重点介绍金属稳态、辅因子组装与线粒体接触位点和嵴组织系统（MICOS）之间重叠的新领域，MICOS介导线粒体生理学的多个方面。重要的是，MICOS复合物可能允许复合物的定位和组织，不仅涉及嵴形成和线粒体内外膜之间的接触，而且还作为金属相关蛋白在辅助因子组装和稳态中协同工作的枢纽。
Metals are key elements for the survival and normal development of humans but can also be toxic to cells when mishandled. In fact, even mild disruption of metal homeostasis causes a wide array of disorders. Many of the metals essential to normal physiology are required in mitochondria for enzymatic activities and for the formation of essential cofactors. Copper is required as a cofactor in the terminal electron transport chain complex cytochrome c oxidase, iron is required for the for the formation of iron-sulfur (Fe-S) clusters and heme, manganese is required for the prevention of oxidative stress production, and these are only a few examples of the critical roles that mitochondrial metals play. Even though the targets of these metals are known, we are still identifying transporters, investigating the roles of known transporters, and defining regulators of the transport process. Mitochondria are dynamic organelles whose content, structure and localization within the cell vary in different tissues and organisms. Our knowledge of the impact that alterations in mitochondrial physiology have on metal content and utilization in these organelles is very limited. The rates of fission and fusion, the ultrastructure of the organelle, and rates of mitophagy can all affect metal homeostasis and cofactor assembly. This review will focus of the emerging areas of overlap between metal homeostasis, cofactor assembly and the mitochondrial contact site and cristae organizing system (MICOS) that mediates multiple aspects of mitochondrial physiology. Importantly the MICOS complexes may allow for localization and organization of complexes not only involved in cristae formation and contact between the inner and outer mitochondrial membranes but also acts as hub for metal-related proteins to work in concert in cofactor assembly and homeostasis.