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Updated: Nov 5, 2025
Ferritinophagy: Assessing the Selective Degradation of Iron by Autophagy in Human Fibroblasts
Published on: February 23, 2024
WDR45 Mutation Impairs the Autophagic Degradation of Transferrin Receptor and Promotes Ferroptosis
Qiuhong Xiong1, Xin Li1, Wenjing Li1
1Institutes of Biomedical Sciences, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, China.
Abstract:
WDR45 is an autophagy-related protein that involves in the formation of autophagosome. Mutations in WDR45 lead to the impairment of autophagy which is associated with the human β-propeller protein-associated neurodegeneration (BPAN). However, the relationship between autophagy and brain iron accumulation in patients with BPAN remains unclear. Here, we demonstrated that transferrin receptor (TfRC) which is critical for the iron import of cells was degraded via autophagy. TfRC was accumulated after the inhibition of autophagy by treatment with autophagic inhibitor chloroquine or knockdown of ATG2A. The intracellular iron content was increased in cells overexpressing TfRC or mutant WDR45, however, ferritin H (FTH) chain was decreased. Increased TfRC and simultaneously decreased FTH consequently resulted in an elevated level of ferrous iron (Fe2+) which further promoted cell ferroptosis, demonstrated by the increased lipid peroxidation and reactive oxygen species (ROS) and the decreased glutathione peroxidase 4 (GPX4) and cell viability. Taken together, these findings provide a piece of important evidence that WDR45 deficiency impairs autophagic degradation of TfRC, therefore leading to iron accumulation, and the elevated iron promotes ferroptosis which may contribute to the progression of BPAN.
Insights
WDR45 deficiency impairs autophagy, leading to iron accumulation via transferrin receptor buildup. This iron overload promotes ferroptosis, potentially driving neurodegeneration in BPAN patients.
Area of Science:
- Neuroscience
- Cell Biology
- Autophagy Research
Background:
- Mutations in WDR45 impair autophagy, linked to beta-propeller protein-associated neurodegeneration (BPAN).
- The precise mechanisms of brain iron accumulation in BPAN are not fully understood.
Purpose of the Study:
- To investigate the role of WDR45 and autophagy in cellular iron homeostasis.
- To elucidate the link between impaired autophagy, iron accumulation, and ferroptosis in the context of BPAN.
Main Methods:
- Investigated the autophagic degradation of transferrin receptor (TfRC).
- Utilized autophagy inhibition (chloroquine) and gene knockdown (ATG2A).
- Assessed intracellular iron levels, ferritin H (FTH) expression, lipid peroxidation, reactive oxygen species (ROS), and glutathione peroxidase 4 (GPX4) activity.
Main Results:
- Transferrin receptor (TfRC) is degraded through autophagy; its levels increase when autophagy is inhibited or WDR45 is mutated.
- WDR45 deficiency or TfRC overexpression leads to increased intracellular iron and decreased FTH.
- Elevated iron promotes ferroptosis, evidenced by increased lipid peroxidation and ROS, and decreased GPX4 and cell viability.
Conclusions:
- WDR45 deficiency disrupts the autophagic degradation of TfRC, causing iron accumulation.
- Increased iron levels promote ferroptosis, contributing to the pathogenesis of BPAN.
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