Wang Juan, Zhao Rongjuan, Ma Jing, Qin Jiangbo, Zhang Huiqiu, Guo Junhong, Chang Xueli, Zhang Wei
Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, China.
First Clinical Medical College, Shanxi Medical University, Taiyuan, China.
Free Radic Biol Med. 2025 Mar 16;230:248-262. doi: 10.1016/j.freeradbiomed.2025.02.012. Epub 2025 Feb 13.
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.
已知FDXR基因的双等位基因突变会导致罕见的线粒体疾病。然而，其潜在的致病机制仍不清楚。本研究调查了一名因FDXR基因复合杂合突变而患有视神经萎缩、共济失调和周围神经病变的患者。在肌肉和神经组织中观察到线粒体结构异常。患者的淋巴细胞系（LCLs）和肌肉样本表现出线粒体功能障碍、铁过载、氧化应激和脂质过氧化的迹象。在LCLs中发现谷胱甘肽过氧化物酶-4失调。此外，用去铁胺、N-乙酰半胱氨酸和铁抑素-1治疗可有效减轻氧化应激和细胞死亡。皮质神经元表明，FDXR缺乏会影响神经突的形态发生。总的来说，这些发现表明铁死亡在FDXR相关疾病的发病机制中起重要作用。此外，艾地苯醌似乎对FDXR突变引起的各种细胞损伤具有保护作用，为FDXR相关疾病的治疗提供了新的见解和治疗方法。
