PDF(Pubmed)
Abstract：
Iron-sulfur clusters (ISC) are essential cofactors that participate in electron transfer, environmental sensing, and catalysis. Amongst the most ancient ISC-containing proteins are the ferredoxin (FDX) family of electron carriers. Humans have two FDXs- FDX1 and FDX2, both of which are localized to mitochondria, and the latter of which is itself important for ISC synthesis. We have previously shown that hypoxia can eliminate the requirement for some components of the ISC biosynthetic pathway, but FDXs were not included in that study. Here, we report that FDX1, but not FDX2, is dispensable under 1% O2 in cultured human cells. We find that FDX1 is essential for production of the lipoic acid cofactor, which is synthesized by the ISC-containing enzyme lipoyl synthase. While hypoxia can rescue the growth phenotype of either FDX1 or lipoyl synthase KO cells, lipoylation in these same cells is not rescued, arguing against an alternative biosynthetic route or salvage pathway for lipoate in hypoxia. Our work reveals the divergent roles of FDX1 and FDX2 in mitochondria, identifies a role for FDX1 in lipoate synthesis, and suggests that loss of lipoic acid can be tolerated under low oxygen tensions in cell culture.
摘要：
铁硫簇（ISC）是参与电子转移的重要辅因子，环境传感，和催化。在最古老的含有ISC的蛋白质中,是电子载体的铁氧还蛋白家族。人类有两种铁氧嘧啶,FDX1和FDX2都位于线粒体，后者本身对ISC合成很重要。我们以前已经表明，缺氧可以消除对ISC生物合成途径某些成分的需求，但该研究中不包括铁皮苷。在这里，我们报告了FDX1，而不是FDX2，在培养的人类细胞中在1％O2下是可有可无的。我们发现FDX1对硫辛酸辅因子的生产至关重要，它是由含有酶脂酰基合酶（LIAS）的ISC合成的。虽然缺氧可以挽救FDX1或LIAS敲除细胞的生长表型，这些相同细胞中的脂肪化没有被拯救，反对低氧条件下硫辛酸的替代生物合成途径或救助途径。我们的工作揭示了FDX1和FDX2在线粒体中的不同作用，确定FDX1在硫辛酸合成中的作用，并表明在细胞培养物中低氧张力下可以耐受硫辛酸的损失。
