Iron–sulfur clusters (Fe–S) are one of the most ancient, ubiquitous and versatile classes of metal cofactors found in nature. Proteins that contain Fe–S clusters constitute one of the largest families of proteins, with varied functions that include electron transport, regulation of gene expression, substrate binding and activation, radical generation, and, more recently discovered, DNA repair. Research during the past two decades has shown that mitochondria are central to the biogenesis of Fe–S clusters in eukaryotic cells via a conserved cluster assembly machinery (ISC assembly machinery) that also controls the synthesis of Fe–S clusters of cytosolic and nuclear proteins. Several key steps for synthesis and trafficking have been determined for mitochondrial Fe–S clusters, as well as the cytosol (CIA – cytosolic iron–sulfur protein assembly), but detailed mechanisms of cluster biosynthesis, transport, and exchange are not well established. Genetic mutations and the instability of certain steps in the biosynthesis and maturation of mitochondrial, cytosolic and nuclear Fe–S cluster proteins affects overall cellular iron homeostasis and can lead to severe metabolic, systemic, neurological and hematological diseases, often resulting in fatality. In this review we briefly summarize the current molecular understanding of both mitochondrial ISC and CIA assembly machineries, and present a comprehensive overview of various associated inborn human disease states.

中文翻译：

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铁硫簇生物合成和运输——对人类疾病的影响

铁硫簇（Fe-S）是自然界中发现的最古老、最普遍、用途最广泛的金属辅助因子之一。含有 Fe-S 簇的蛋白质构成了最大的蛋白质家族之一，具有多种功能，包括电子传输、基因表达调节、底物结合和激活、自由基生成以及最近发现的 DNA 修复。过去二十年的研究表明，线粒体是真核细胞中 Fe-S 簇生物发生的核心，通过保守的簇组装机制（ISC 组装机制）控制胞质和核蛋白 Fe-S 簇的合成。线粒体 Fe-S 簇以及细胞质（CIA——细胞质铁硫蛋白组装）的合成和运输的几个关键步骤已经确定，但簇生物合成、运输和交换的详细机制尚未确定。基因突变以及线粒体、细胞质和核 Fe-S 簇蛋白生物合成和成熟中某些步骤的不稳定性会影响整体细胞铁稳态，并可能导致严重的代谢、全身、神经和血液疾病，常常导致死亡。在这篇综述中，我们简要总结了目前对线粒体 ISC 和 CIA 组装机制的分子理解，并全面概述了各种相关的人类先天疾病状态。