MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2.
MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2.
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DOI：
10.1016/j.cmet.2009.08.015
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发表时间：
2009-10
期刊：
影响因子：
29
通讯作者：
Loscalzo J
中科院分区：
文献类型：
--
作者：
Chan SY;Zhang YY;Hemann C;Mahoney CE;Zweier JL;Loscalzo J
线粒体呼吸抑制代表了一种进化上古老的细胞对缺氧的适应，并深刻地影响细胞的生存和功能;然而，其潜在的分子机制尚未完全了解。首先利用肺动脉内皮细胞作为代表性缺氧细胞类型，我们确定铁硫簇组装蛋白（ISCU 1/2）作为缺氧诱导的microRNA-210（miR-210）抑制的直接靶点。ISCU 1/2促进铁硫簇的组装，这些簇是电子传递和线粒体氧化还原反应的关键辅基。在上调miR-210和抑制ISCU 1/2的体内条件下，铁硫簇的完整性被破坏。反过来，通过在缺氧期间抑制ISCU 1/2，miR-210降低了控制线粒体代谢的原型铁硫蛋白的活性，包括复合物I和顺乌头酸酶。因此，miR-210抑制线粒体呼吸和相关的下游功能。这些结果确定了microRNA，铁硫簇生物学，缺氧和线粒体功能之间的重要机制联系，对细胞代谢和适应细胞应激具有广泛的意义。
Repression of mitochondrial respiration represents an evolutionarily ancient cellular adaptation to hypoxia and profoundly influences cell survival and function; however, the underlying molecular mechanisms are incompletely understood. Primarily utilizing pulmonary arterial endothelial cells as a representative hypoxic cell type, we identify the iron-sulfur cluster assembly proteins (ISCU1/2) as direct targets for repression by the hypoxia-induced microRNA-210 (miR-210). ISCU1/2 facilitate the assembly of iron-sulfur clusters, prosthetic groups that are critical for electron transport and mitochondrial oxidation-reduction reactions. Under in vivo conditions of up-regulating miR-210 and repressing ISCU1/2, the integrity of iron-sulfur clusters is disrupted. In turn, by repressing ISCU1/2 during hypoxia, miR-210 decreases the activity of prototypical iron-sulfur proteins controlling mitochondrial metabolism, including Complex I and aconitase. Consequently, miR-210 represses mitochondrial respiration and associated downstream functions. These results identify important mechanistic connections among microRNA, iron-sulfur cluster biology, hypoxia, and mitochondrial function, with broad implications for cellular metabolism and adaptation to cellular stress.
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