Journal Article

FTH1 Inhibits Ferroptosis Through Ferritinophagy in the 6-OHDA Model of Parkinson's Disease

Li, Hang, Kuang, Weihong, Hao, Xiaoqian, Li, Xinrong, Liu, Xuelei, Zhu, Meiling, Lu, Juan, Zhang, Guiyu, Zhao, Caiping, Tian, Ye, Chen, Dongfeng

2020

Overview

Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons associated with dysregulation of iron homeostasis in the brain. Ferroptosis is an iron-dependent cell death process that serves as a significant regulatory mechanism in PD. However, its underlying mechanisms are not yet fully understood. By performing RNA sequencing analysis, we found that the main iron storage protein ferritin heavy chain 1 (FTH1) is differentially expressed in the rat 6-hydroyxdopamine (6-OHDA) model of PD compared with control rats. Our present work demonstrates that FTH1 is involved in iron accumulation and the ferroptosis pathway in this model. Knockdown of FTH1 in PC-12 cells significantly inhibited cell viability and caused mitochondrial dysfunction. Moreover, FTH1 was found to be involved in ferritinophagy, a selective form of autophagy involving the degradation of ferritin by ferroptosis. Overexpression of FTH1 in PC-12 cells impaired ferritinophagy and downregulated microtubule-associated protein light chain 3 and nuclear receptor coactivator 4 expression, ultimately suppressing cell death induced by ferroptosis. Consistent with these findings, the ferritinophagy inhibitors chloroquine and bafilomycin A1 inhibited ferritin degradation and ferroptosis in 6-OHDA-treated PC-12 cells. This entire process was mediated by the cyclic regulation of FTH1 and ferritinophagy. Taken together, these results suggest that FTH1 links ferritinophagy and ferroptosis in the 6-OHDA model of PD, and provide a new perspective and potential for a pharmacological target in this disease.

• Publisher: Elsevier Inc,Springer International Publishing,Springer Nature B.V
• Subject: Animals / Apoptosis / Autophagy / Biomedical and Life Sciences / Biomedicine / Cell death / Cell Survival - drug effects / Cell Survival - physiology / Cell viability / Chloroquine / Dopamine receptors / Ferritin / ferritinophagy / Ferritins - biosynthesis / Ferritins - genetics / Ferroptosis / Ferroptosis - drug effects / Ferroptosis - physiology / FTH1 / Homeostasis / Iron / Male / Mitochondria / Movement disorders / Neurobiology / Neurodegeneration / Neurodegenerative diseases / Neurology / Neurosciences / Neurosurgery / Original / Original Article / Oxidopamine - toxicity / Oxidoreductases - biosynthesis / Oxidoreductases - genetics / Parkinson's disease / Parkinsonian Disorders - chemically induced / Parkinsonian Disorders - genetics / Parkinsonian Disorders - metabolism / PC12 Cells / Phagocytosis / Rats / Rats, Sprague-Dawley / Ribonucleic acid / RNA / Sequence analysis