Schiavi Alfonso, Salveridou Eva, Brinkmann Vanessa, Shaik Anjumara, Menzel Ralph, Kalyanasundaram Sumana, Nygård Ståle, Nilsen Hilde, Ventura Natascia
Leibniz Research Institute for Environmental Medicine (IUF), Düsseldorf, Germany.
Humboldt-Universität zu Berlin, Berlin, Germany.
iScience. 2023 Mar 21;26(4):106448. doi: 10.1016/j.isci.2023.106448. eCollection 2023 Apr 21.
Excessive iron accumulation or deficiency leads to a variety of pathologies in humans and developmental arrest in the nematode . Instead, sub-lethal iron depletion extends lifespan. Hypoxia preconditioning protects against severe hypoxia-induced neuromuscular damage across species but it has low feasible application. In this study, we assessed the potential beneficial effects of genetic and chemical interventions acting via mild iron instead of oxygen depletion. We show that limiting iron availability in through frataxin silencing or the iron chelator bipyridine, similar to hypoxia preconditioning, protects against hypoxia-, age-, and proteotoxicity-induced neuromuscular deficits. Mechanistically, our data suggest that the beneficial effects elicited by frataxin silencing are in part mediated by counteracting ferroptosis, a form of non-apoptotic cell death mediated by iron-induced lipid peroxidation. This is achieved by impacting on different key ferroptosis players and likely via -independent redox systems. We thus point to ferroptosis inhibition as a novel potential strategy to promote healthy aging.
铁的过度积累或缺乏会导致人类出现多种病理状况，并使线虫发育停滞。相反，亚致死性铁耗竭可延长寿命。缺氧预处理可保护不同物种免受严重缺氧诱导的神经肌肉损伤，但实际应用可行性较低。在本研究中，我们评估了通过轻度铁耗竭而非氧耗竭进行基因和化学干预的潜在有益效果。我们发现，通过沉默frataxin或使用铁螯合剂联吡啶来限制铁的可利用性，类似于缺氧预处理，可保护机体免受缺氧、衰老和蛋白毒性诱导的神经肌肉功能缺陷。从机制上讲，我们的数据表明，沉默frataxin所产生的有益效果部分是通过对抗铁死亡来介导的，铁死亡是一种由铁诱导的脂质过氧化介导的非凋亡性细胞死亡形式。这是通过影响不同的关键铁死亡相关因子并可能通过独立于 的氧化还原系统来实现的。因此，我们指出抑制铁死亡是促进健康衰老的一种新的潜在策略。
