Abstract:
The progression of human degenerative and hypoxic/ischemic diseases is accompanied by widespread cell death. One death process linking iron-catalyzed reactive species with lipid peroxidation is ferroptosis, which shows hallmarks of both programmed and necrotic death in vitro. While evidence of ferroptosis in neurodegenerative disease is indicated by iron accumulation and involvement of lipids, a stable marker for ferroptosis has not been identified. Its prevalence is thus undetermined in human pathophysiology, impeding recognition of disease areas and clinical investigations with candidate drugs. Here, we identified ferroptosis marker antigens by analyzing surface protein dynamics and discovered a single protein, Fatty Acid-Binding Protein 5 (FABP5), which was stabilized at the cell surface and specifically elevated in ferroptotic cell death. Ectopic expression and lipidomics assays demonstrated that FABP5 drives redistribution of redox-sensitive lipids and ferroptosis sensitivity in a positive-feedback loop, indicating a role as a functional biomarker. Notably, immunodetection of FABP5 in mouse stroke penumbra and in hypoxic postmortem patients was distinctly associated with hypoxically damaged neurons. Retrospective cell death characterized here by the novel ferroptosis biomarker FABP5 thus provides first evidence for a long-hypothesized intrinsic ferroptosis in hypoxia and inaugurates a means for pathological detection of ferroptosis in tissue.
摘要:
人类退行性疾病和缺氧/缺血性疾病的进展伴随着广泛的细胞死亡。将铁催化的反应性物种与脂质过氧化联系起来的一个死亡过程是铁凋亡,显示了体外程序性死亡和坏死性死亡的标志。虽然铁的积累和脂质的参与表明了神经退行性疾病中铁死亡的证据,铁死亡的稳定标记尚未确定。因此,在人类病理生理学中,其患病率尚未确定,阻碍对疾病领域的识别和候选药物的临床研究。这里,我们通过分析表面蛋白动力学鉴定了铁凋亡标记抗原,并发现了单一蛋白,脂肪酸结合蛋白5(FABP5),稳定在细胞表面,并在铁细胞死亡中特异性升高。异位表达和脂质组学测定表明,FABP5在正反馈回路中驱动氧化还原敏感脂质和铁凋亡敏感性的重新分布,表明作为功能性生物标志物的作用。值得注意的是,在小鼠中风半暗带和缺氧的死后患者中,FABP5的免疫检测与缺氧损伤的神经元明显相关。本文以新颖的铁凋亡生物标志物FABP5为特征的回顾性细胞死亡因此提供了在缺氧中长期假设的内在铁凋亡的第一个证据,并开创了组织中铁凋亡的病理检测方法。