Autolysosomal exocytosis of lipids protect neurons from ferroptosis.
Autolysosomal exocytosis of lipids protect neurons from ferroptosis.
复制标题
DOI：
10.1083/jcb.202207130
复制
发表时间：
2023-06-05
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
拉尔汗等人。表明神经元在氧化应激期间通过自溶酶体胞吐作用以富含脂质的颗粒形式释放过氧化脂质和铁。这可以保护神经元免受铁死亡引起的细胞死亡。在氧化应激期间，神经元释放被神经胶质细胞内化的脂质。这一协调过程的缺陷在多种神经退行性疾病中发挥着重要作用。然而，脂质释放的机制及其对神经元健康的影响尚不清楚。在这里，我们证明自溶酶体胞吐作用释放的脂质蛋白颗粒可以保护神经元免受铁死亡（一种由脂质过氧化驱动的细胞死亡形式）。我们发现，在氧化应激过程中，过氧化脂质和铁通过自溶酶体胞吐作用从神经元中释放，这需要胞吐机制 VAMP7 和突触蛋白 4。我们通过 TEM 观察膜结合脂质蛋白颗粒，并使用冷冻电镜证明这些颗粒从神经元中释放。未能释放这些脂质蛋白颗粒会导致脂质氢过氧化物和铁积累，并使神经元对铁死亡敏感。我们的结果揭示了神经元如何保护自己免受过氧化脂质的侵害。考虑到涉及铁死亡的脑部病理的数量，该途径的缺陷可能在神经退行性疾病的病理生理学中发挥关键作用。
Ralhan et al. show that neurons release peroxidated lipids and iron as lipid-rich particles by autolysosomal exocytosis during oxidative stress. This protects neurons from cell death by ferroptosis. During oxidative stress neurons release lipids that are internalized by glia. Defects in this coordinated process play an important role in several neurodegenerative diseases. Yet, the mechanisms of lipid release and its consequences on neuronal health are unclear. Here, we demonstrate that lipid-protein particle release by autolysosome exocytosis protects neurons from ferroptosis, a form of cell death driven by lipid peroxidation. We show that during oxidative stress, peroxidated lipids and iron are released from neurons by autolysosomal exocytosis which requires the exocytic machinery VAMP7 and syntaxin 4. We observe membrane-bound lipid-protein particles by TEM and demonstrate that these particles are released from neurons using cryoEM. Failure to release these lipid-protein particles causes lipid hydroperoxide and iron accumulation and sensitizes neurons to ferroptosis. Our results reveal how neurons protect themselves from peroxidated lipids. Given the number of brain pathologies that involve ferroptosis, defects in this pathway likely play a key role in the pathophysiology of neurodegenerative disease.
登录
查看更多内容
影响因子：
14.8
作者：
Kagan VE;Mao G;Qu F;Angeli JP;Doll S;Croix CS;Dar HH;Liu B;Tyurin VA;Ritov VB;Kapralov AA;Amoscato AA;Jiang J;Anthonymuthu T;Mohammadyani D;Yang Q;Proneth B;Klein-Seetharaman J;Watkins S;Bahar I;Greenberger J;Mallampalli RK;Stockwell BR;Tyurina YY;Conrad M;Bayır H
通讯作者：
Bayır H
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：
29
作者：
Liu L;MacKenzie KR;Putluri N;Maletić-Savatić M;Bellen HJ
通讯作者：
Bellen HJ
影响因子：
3.7
作者：
Hedlund M;Nagaeva O;Kargl D;Baranov V;Mincheva-Nilsson L
通讯作者：
Mincheva-Nilsson L
影响因子：
4
作者：
Fote GM;Geller NR;Efstathiou NE;Hendricks N;Vavvas DG;Reidling JC;Thompson LM;Steffan JS
通讯作者：
Steffan JS