MicroRNA-210 decreases heme levels by targeting ferrochelatase in cardiomyocytes.
MicroRNA-210 decreases heme levels by targeting ferrochelatase in cardiomyocytes.
复制标题
DOI：
10.1161/jaha.113.000121
复制
发表时间：
2013-04-22
影响因子：
5.4
通讯作者：
Ardehali H
中科院分区：
文献类型：
--
作者：
Qiao A;Khechaduri A;Kannan Mutharasan R;Wu R;Nagpal V;Ardehali H
MicroRNA-210 (miR-210) 通过调节铁硫簇组装蛋白 (ISCU1/2)（一种参与 Fe/S 簇合成的蛋白质）来增加缺氧并调节线粒体呼吸。然而，目前尚不清楚 miR-210 如何影响细胞铁水平或血红素的产生，血红素是细胞和线粒体功能所需的另一种含铁分子。为了筛选受铁调节的微核糖核酸 (miRNA)，我们在用铁螯合剂处理的新生大鼠心肌细胞中进行了 miRNA 基因阵列。铁螯合后 miR-210 的水平显着增加，然而，这种反应完全是通过缺氧诱导因子 (HIF) 途径介导的。此外，miR-210通过调节亚铁螯合酶（FECH）（血红素生物合成中的最后一种酶）降低细胞血红素水平以及线粒体和胞质含血红素蛋白的活性。 FECH 3′非翻译区 (UTR) 中 2 个 miR-210 结合位点的突变逆转了 miR-210 反应，而任一结合位点的单独突变均未产生任何影响。血红素和 FECH 中 miR-210 介导的变化独立于 ISCU，因为缺乏 3'UTR 的 ISCU 构建体的过表达不会改变 miR-210 对血红素和 FECH 的调节。最后，FECH 水平在缺氧时增加，并且这种效应不会被 miR-210 敲除所逆转，这表明 miR-210 对血红素的影响仅限于含氧量正常的条件，并且该途径在缺氧时被覆盖。我们的结果确定了 miR-210 在常氧条件下通过靶向和抑制 FECH 在调节血红素产生中的作用。
MicroRNA‐210 (miR‐210) increases in hypoxia and regulates mitochondrial respiration through modulation of iron‐sulfur cluster assembly proteins (ISCU1/2), a protein that is involved in Fe/S cluster synthesis. However, it is not known how miR‐210 affects cellular iron levels or production of heme, another iron containing molecule that is also needed for cellular and mitochondrial function. To screen for micro‐ribonucleic acids (miRNAs) regulated by iron, we performed a miRNA gene array in neonatal rat cardiomyocytes treated with iron chelators. Levels of miR‐210 are significantly increased with iron chelation, however, this response was mediated entirely through the hypoxia‐inducible factor (HIF) pathway. Furthermore, miR‐210 reduced cellular heme levels and the activity of mitochondrial and cytosolic heme‐containing proteins by modulating ferrochelatase (FECH), the last enzyme in heme biosynthesis. Mutation of the 2 miR‐210 binding sites in the 3′ untranslated region (UTR) of FECH reversed the miR‐210 response, while mutation of either binding site in isolation did not exert any effects. Changes mediated by miR‐210 in heme and FECH were independent of ISCU, as overexpression of an ISCU construct lacking the 3′ UTR does not alter miR‐210 regulation of heme and FECH. Finally, FECH levels increased in hypoxia, and this effect was not reversed by miR‐210 knockdown, suggesting that the effects of miR‐210 on heme are restricted to normoxic conditions, and that the pathway is overriden in hypoxia. Our results identify a role for miR‐210 in the regulation of heme production by targeting and inhibiting FECH under normoxic conditions.