Role of Mitochondria in Ferroptosis
Role of Mitochondria in Ferroptosis
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线粒体在铁死亡中的作用
DOI：
10.1016/j.molcel.2018.10.042
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发表时间：
2019-01-17
期刊：
影响因子：
16
通讯作者：
Jiang, Xuejun
中科院分区：
文献类型：
--
作者：
Gao, Minghui;Yi, Junmei;Jiang, Xuejun
铁凋亡是由铁依赖性脂质过氧化驱动的调节性坏死过程。虽然铁凋亡和细胞代谢相互作用，线粒体是否参与铁凋亡仍有争议。在这里，我们表明，线粒体发挥了至关重要的作用，半胱氨酸剥夺诱导的铁凋亡，但不是在诱导抑制谷胱甘肽过氧化物酶-4（GPX 4），最下游的铁凋亡途径的组成部分。从机制上讲，半胱氨酸剥夺导致线粒体膜电位超极化和脂质过氧化物积累。抑制线粒体TCA循环或电子传递链（ETC）减轻线粒体膜电位超极化，脂质过氧化物积累，和铁凋亡。阻断氨解具有相同的抑制作用，这是抵消了下游TCA循环中间体的供应。重要的是，富马酸水合酶（一种肿瘤抑制因子和TCA循环组分）功能的丧失赋予了对半胱氨酸剥夺诱导的铁凋亡的抗性。总的来说，这项工作证明了线粒体在半胱氨酸剥夺诱导的铁凋亡中的关键作用，并暗示了铁凋亡在肿瘤抑制中的作用。
Ferroptosis is a regulated necrosis process driven by iron-dependent lipid peroxidation. Although ferroptosis and cellular metabolism interplay with one another, whether mitochondria are involved in ferroptosis is under debate. Here, we demonstrate that mitochondria play a crucial role in cysteinedeprivation-induced ferroptosis but not in that induced by inhibiting glutathione peroxidase-4 (GPX4), the most downstream component of the ferroptosis pathway. Mechanistically, cysteine deprivation leads to mitochondrial membrane potential hyperpolarization and lipid peroxide accumulation. Inhibition of mitochondrial TCA cycle or electron transfer chain (ETC) mitigated mitochondrial membrane potential hyperpolarization, lipid peroxide accumulation, and ferroptosis. Blockage of glutaminolysis had the same inhibitory effect, which was counteracted by supplying downstream TCA cycle intermediates. Importantly, loss of function of fumarate hydratase, a tumor suppressor and TCA cycle component, confers resistance to cysteine-deprivation-induced ferroptosis. Collectively, this work demonstrates the crucial role of mitochondria in cysteine-deprivation-induced ferroptosis and implicates ferroptosis in tumor suppression.