Dynamic O-GlcNAcylation coordinates ferritinophagy and mitophagy to activate ferroptosis.
Dynamic O-GlcNAcylation coordinates ferritinophagy and mitophagy to activate ferroptosis.
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动态O-GlcNAc糖基化协调铁蛋白自噬和线粒体自噬以激活铁死亡
DOI：
10.1038/s41421-022-00390-6
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发表时间：
2022-05-03
期刊：
影响因子：
33.5
通讯作者：
Chen Q
中科院分区：
文献类型：
--
作者：
Yu F;Zhang Q;Liu H;Liu J;Yang S;Luo X;Liu W;Zheng H;Liu Q;Cui Y;Chen G;Li Y;Huang X;Yan X;Zhou J;Chen Q
铁凋亡是一种以脂质过氧化积累为特征的调节性铁依赖性细胞死亡。氨基酸，脂质，氧化还原和铁代谢的无数方面被发现驱动或抑制铁凋亡的执行。然而，细胞如何破译不同的促铁凋亡应激激活铁凋亡仍然难以捉摸。在这里，我们报告，蛋白质O-GlcNAc酰化，葡萄糖流量的主要营养传感器，协调铁蛋白和线粒体自噬的铁凋亡。在铁凋亡刺激物如RSL 3（一种常用的铁凋亡诱导剂）处理后，存在蛋白质O-GlcNAc酰化的双相变化以调节铁凋亡。药理学或遗传抑制O-GlcNAc化促进铁蛋白吞噬，导致不稳定铁向线粒体积累。抑制O-GlcNAc酰化导致线粒体断裂和线粒体自噬增强，提供了额外的不稳定铁源，使细胞对铁凋亡更敏感。从机制上讲，我们发现铁蛋白重链在S179处的去-O-GlcNAc酰化促进了其与NCOA 4（铁蛋白吞噬受体）的相互作用，从而积累了用于铁凋亡的不稳定铁。我们的研究结果揭示了一个以前未描述的动态O-GlcNAc酰化与铁代谢和铁凋亡决策的联系，从而为对抗疾病提供了潜在的治疗干预。
Ferroptosis is a regulated iron-dependent cell death characterized by the accumulation of lipid peroxidation. A myriad of facets linking amino acid, lipid, redox, and iron metabolisms were found to drive or to suppress the execution of ferroptosis. However, how the cells decipher the diverse pro-ferroptotic stress to activate ferroptosis remains elusive. Here, we report that protein O-GlcNAcylation, the primary nutrient sensor of glucose flux, orchestrates both ferritinophagy and mitophagy for ferroptosis. Following the treatment of ferroptosis stimuli such as RSL3, a commonly used ferroptosis inducer, there exists a biphasic change of protein O-GlcNAcylation to modulate ferroptosis. Pharmacological or genetic inhibition of O-GlcNAcylation promoted ferritinophagy, resulting in the accumulation of labile iron towards mitochondria. Inhibition of O-GlcNAcylation resulted in mitochondria fragmentation and enhanced mitophagy, providing an additional source of labile iron and rendering the cell more sensitive to ferroptosis. Mechanistically, we found that de-O-GlcNAcylation of the ferritin heavy chain at S179 promoted its interaction with NCOA4, the ferritinophagy receptor, thereby accumulating labile iron for ferroptosis. Our findings reveal a previously uncharacterized link of dynamic O-GlcNAcylation with iron metabolism and decision-making for ferroptosis, thus offering potential therapeutic intervention for fighting disease.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
5.5
作者：
Chen X;Yu C;Kang R;Tang D
通讯作者：
Tang D
DOI：
10.1016/j.bbamcr.2016.09.008
发表时间：
2016-12-01
影响因子：
5.1
作者：
Hamdi, Arnel;Roshan, Tariq M.;Ponka, Prem
通讯作者：
Ponka, Prem
影响因子：
3
作者：
Chatham, John C.;Marchase, Richard B.
通讯作者：
Marchase, Richard B.
影响因子：
21.3
作者：
Friedmann Angeli JP;Schneider M;Proneth B;Tyurina YY;Tyurin VA;Hammond VJ;Herbach N;Aichler M;Walch A;Eggenhofer E;Basavarajappa D;Rådmark O;Kobayashi S;Seibt T;Beck H;Neff F;Esposito I;Wanke R;Förster H;Yefremova O;Heinrichmeyer M;Bornkamm GW;Geissler EK;Thomas SB;Stockwell BR;O'Donnell VB;Kagan VE;Schick JA;Conrad M
通讯作者：
Conrad M