Iron loss triggers mitophagy through induction of mitochondrial ferritin
Iron loss triggers mitophagy through induction of mitochondrial ferritin
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DOI：
10.15252/embr.202050202
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发表时间：
2020-09-25
期刊：
影响因子：
7.7
通讯作者：
Hino, Keisuke
中科院分区：
文献类型：
--
作者：
Hara, Yuichi;Yanatori, Izumi;Hino, Keisuke
线粒体质量是通过线粒体自噬选择性去除受损的线粒体来控制的。线粒体自噬损伤与衰老和许多病理状况有关。铁螯合剂引起的铁损失通过一种未知的机制触发线粒体自噬。这种类型的线粒体自噬可能具有治疗潜力，因为铁螯合剂在临床上使用。在这里，我们的目的是澄清铁损失诱导线粒体自噬的机制。去铁酮（一种铁螯合剂）处理导致线粒体铁蛋白（FTMT）的表达增加和FTMT前体在线粒体外膜上的定位。特异性蛋白1及其调节因子低氧诱导因子1 α是地菲力酮诱导FTMT增加所必需的。FTMT特异性地与核受体辅激活因子4（一种自噬货物受体）相互作用。去极化的线粒体选择性地发生地菲力酮诱导的线粒体自噬。此外，去铁酮通过诱导线粒体自噬抑制小鼠肝细胞癌（HCC）的发展。沉默FTMT消除了去铁酮诱导的线粒体自噬和对HCC的抑制。这些结果证明了铁损失诱导线粒体自噬的机制，并为靶向线粒体自噬激活作为治疗策略提供了理论基础。
Mitochondrial quality is controlled by the selective removal of damaged mitochondria through mitophagy. Mitophagy impairment is associated with aging and many pathological conditions. An iron loss induced by iron chelator triggers mitophagy by a yet unknown mechanism. This type of mitophagy may have therapeutic potential, since iron chelators are clinically used. Here, we aimed to clarify the mechanisms by which iron loss induces mitophagy. Deferiprone, an iron chelator, treatment resulted in the increased expression of mitochondrial ferritin (FTMT) and the localization of FTMT precursor on the mitochondrial outer membrane. Specific protein 1 and its regulator hypoxia-inducible factor 1 alpha were necessary for deferiprone-induced increase in FTMT. FTMT specifically interacted with nuclear receptor coactivator 4, an autophagic cargo receptor. Deferiprone-induced mitophagy occurred selectively for depolarized mitochondria. Additionally, deferiprone suppressed the development of hepatocellular carcinoma (HCC) in mice by inducing mitophagy. Silencing FTMT abrogated deferiprone-induced mitophagy and suppression of HCC. These results demonstrate the mechanisms by which iron loss induces mitophagy and provide a rationale for targeting mitophagic activation as a therapeutic strategy.