英国剑桥大学David C. Rubinsztein研究小组发现，神经退行性变中WIPI4的缺失会导致自噬非依赖性铁死亡。2024年3月7日，《自然—细胞生物学》杂志在线发表了这项成果。

研究人员表示，β-螺旋桨蛋白相关神经变性（BPAN）是一种罕见的X连锁显性遗传病，是表现为神经变性和脑铁积聚的几种疾病之一。编码WIPI4的WD重复结构域45（WDR45）基因发生突变会导致BPAN功能丧失，但这些突变如何引发病变的细胞机制尚不清楚。文献中的主流观点认为，鉴于WIPI4在自噬降解途径中发挥作用，BPAN只是自噬缺乏的结果。

然而，研究人员的数据表明，正如在细胞培养和斑马鱼体内所证明的那样，WIPI4的缺失会通过一种自噬无关的机制导致铁死亡——一种由脂质过氧化诱导的细胞死亡类型。WIPI4的耗竭会增加ATG2A在内质网-线粒体接触点的定位，从而加强磷脂酰丝氨酸向线粒体的输入。这导致线粒体合成的磷脂酰乙醇胺增加，而磷脂酰乙醇胺是一种容易发生过氧化反应的主要脂质，从而使铁死亡成为可能。这种机制与经典的铁死亡反应刺激重叠极少，但却能让人深入了解BPAN神经变性的原因，并为治疗策略提供线索。

附：英文原文

Title: Loss of WIPI4 in neurodegeneration causes autophagy-independent ferroptosis

Author: Zhu, Ye, Fujimaki, Motoki, Snape, Louisa, Lopez, Ana, Fleming, Angeleen, Rubinsztein, David C.

Issue&Volume: 2024-03-07

Abstract: β-Propeller protein-associated neurodegeneration (BPAN) is a rare X-linked dominant disease, one of several conditions that manifest with neurodegeneration and brain iron accumulation. Mutations in the WD repeat domain 45 (WDR45) gene encoding WIPI4 lead to loss of function in BPAN but the cellular mechanisms of how these trigger pathology are unclear. The prevailing view in the literature is that BPAN is simply the consequence of autophagy deficiency given that WIPI4 functions in this degradation pathway. However, our data indicate that WIPI4 depletion causes ferroptosis—a type of cell death induced by lipid peroxidation—via an autophagy-independent mechanism, as demonstrated both in cell culture and in zebrafish. WIPI4 depletion increases ATG2A localization at endoplasmic reticulum–mitochondrial contact sites, which enhances phosphatidylserine import into mitochondria. This results in increased mitochondrial synthesis of phosphatidylethanolamine, a major lipid prone to peroxidation, thus enabling ferroptosis. This mechanism has minimal overlap with classical ferroptosis stimuli but provides insights into the causes of neurodegeneration in BPAN and may provide clues for therapeutic strategies.

DOI: 10.1038/s41556-024-01373-3

Source: https://www.nature.com/articles/s41556-024-01373-3