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Updated: May 27, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
Biallelic FDXR mutations induce ferroptosis in a rare mitochondrial disease with ataxia
Juan Wang1, Rongjuan Zhao1, Jing Ma2
1Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, China.
Abstract:
Biallelic mutations in the FDXR are known to cause rare mitochondrial diseases. However, the underlying pathogenic mechanisms remain elusive. This study investigated a patient affected by optic atrophy, ataxia, and peripheral neuropathy resulting from compound heterozygous mutations in FDXR. Structural abnormalities in mitochondria were observed in muscle and nerve tissues. Lymphoblastic cell lines (LCLs) and muscle samples from the patient exhibited signs of mitochondrial dysfunction, iron overload, oxidative stress, and lipid peroxidation. Dysregulation of the glutathione peroxidase-4 was noted in the LCLs. Furthermore, treatment with deferoxamine, N-acetyl-cysteine, and ferrostatin-1 effectively alleviated oxidative stress and cell death. Cortical neurons demonstrate that FDXR deficiency impacts the morphogenesis of neurites. Collectively, these findings suggest that ferroptosis plays a significant role in the pathogenesis of FDXR-associated diseases. Additionally, idebenone appeared to have protective effects against various cellular injuries induced by FDXR mutations, providing novel insights and therapeutic approaches for the treatment of FDXR-associated diseases.
Insights
Mutations in the FDXR gene cause rare mitochondrial diseases. This study reveals ferroptosis, a form of cell death, is a key mechanism in FDXR-associated disorders, suggesting new therapeutic avenues.
Area of Science:
- Mitochondrial Biology
- Neurogenetics
- Cell Death Mechanisms
Background:
- Biallelic mutations in the FDXR gene are associated with rare mitochondrial diseases.
- The precise pathogenic mechanisms underlying FDXR-related disorders are not fully understood.
Purpose of the Study:
- To investigate the molecular mechanisms of FDXR-associated mitochondrial disease in a patient with optic atrophy, ataxia, and peripheral neuropathy.
- To explore the role of ferroptosis in the pathogenesis of FDXR deficiency.
Main Methods:
- Analysis of patient muscle and nerve tissues for mitochondrial structural abnormalities.
- Assessment of lymphoblastic cell lines (LCLs) and muscle samples for mitochondrial dysfunction, iron overload, oxidative stress, and lipid peroxidation.
- Evaluation of the impact of FDXR deficiency on cortical neuron neurite morphogenesis and the efficacy of therapeutic agents.
Main Results:
- Patient tissues and LCLs displayed mitochondrial dysfunction, iron overload, oxidative stress, and lipid peroxidation.
- Dysregulation of glutathione peroxidase-4 was observed in LCLs.
- Treatment with deferoxamine, N-acetyl-cysteine, and ferrostatin-1 reduced oxidative stress and cell death; idebenone showed protective effects.
Conclusions:
- Ferroptosis is implicated as a significant pathogenic mechanism in FDXR-associated diseases.
- FDXR deficiency impairs neurite morphogenesis in cortical neurons.
- Idebenone demonstrates potential as a therapeutic agent for FDXR-related cellular injuries.
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