The First Affiliated Hospital, Institute of Neurology, Hengyang Medical School, 574417University of South China, Hengyang, P. R. China.
Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hengyang Medical School, University of South China, Hengyang, Hunan, P. R. China.
Toxicol Ind Health. 2021 Nov;37(11):685-694. doi: 10.1177/07482337211048582. Epub 2021 Oct 13.
Formaldehyde (FA) causes neurotoxicity and contributes to the occurrence of neurodegenerative diseases. However, the mechanism of FA-induced neurotoxicity has not been fully elucidated. Ferritinophagy, an autophagy process of ferritin mediated by the nuclear receptor coactivator 4 (NCOA4), is a potential mechanism of neurotoxicity. In this study, we explored whether ferritinophagy is associated with the neurotoxicity of FA. Our results showed that FA (50, 100, 200 μM; 24 h) exposure upregulated ferritinophagy in the mouse hippocampal neuronal HT22 cells, which was evidenced by the upregulated autophagic flux, the increased colocalizations of NCOA4 with ferritin heavy chain (FTH1) and NCOA4 with microtubule-associated protein 1 light chain-3B (LC3B), the augmented expression of NCOA4, and the reduced content of FTH1. We also found that FA (0.1, 1, and 10 μmol, i.c.v., 7d) administration boosted ferritinophagy in the hippocampus of Sprague-Dawley (SD) rats, which was demonstrated by the accumulated autophagosomes, the increased expressions of LC3II/I and NCOA4, and the decreased contents of p62 and FTH1 in the hippocampus. Further, we confirmed that inhibition of ferritinophagy by silencing the expression of NCOA4 decreased FA-induced toxic damage in HT22 cells. These results indicated that FA induces neurotoxicity by promoting ferritinophagy. Our findings suggest a potential mechanism insight into the FA-induced neurotoxicity, which in turn provides a new thought for the treatment of FA-related neurodegenerative diseases.
甲醛（FA）可导致神经毒性，并促成神经退行性疾病的发生。然而，FA 诱导的神经毒性的机制尚未完全阐明。铁蛋白自噬是一种由核受体共激活因子 4（NCOA4）介导的铁蛋白自噬过程，是神经毒性的潜在机制。在本研究中，我们探讨了铁蛋白自噬是否与 FA 的神经毒性有关。结果表明，FA（50、100、200 μM；24 h）暴露可上调 HT22 细胞中的铁蛋白自噬，这表现在自噬流增加、NCOA4 与铁蛋白重链（FTH1）和 NCOA4 与微管相关蛋白 1 轻链 3B（LC3B）的共定位增加、NCOA4 的表达增加和 FTH1 的含量减少。我们还发现，FA（0.1、1 和 10 μmol，侧脑室注射，7 d）给药可增强 SD 大鼠海马中的铁蛋白自噬，这表现在自噬体积累增加、LC3II/I 和 NCOA4 的表达增加以及 p62 和 FTH1 的含量减少。此外，我们证实通过沉默 NCOA4 的表达抑制铁蛋白自噬可降低 FA 诱导的 HT22 细胞毒性损伤。这些结果表明 FA 通过促进铁蛋白自噬导致神经毒性。我们的研究结果提示了 FA 诱导的神经毒性的潜在机制，这为治疗与 FA 相关的神经退行性疾病提供了新的思路。
