Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA, 45229.
Division of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA, 45229.
Cell Death Dis. 2020 Jun 4;11(6):423. doi: 10.1038/s41419-020-2637-3.
The mitochondrial flavoprotein ferredoxin reductase (FDXR) is required for biogenesis of iron-sulfur clusters and for steroidogenesis. Iron-sulfur (Fe-S) clusters are ubiquitous cofactors essential to various cellular processes, and an increasing number of disorders are associated with disruptions in the synthesis of Fe-S clusters. Our previous studies have demonstrated that hypomorphic mutations in FDXR cause a novel mitochondriopathy and optic atrophy in humans and mice, attributed in part to reduced function of the electron transport chain (ETC) as well as elevated production of reactive oxygen species (ROS). Inflammation and peripheral neuropathy are also hallmarks of this disease. In this paper, we demonstrate that FDXR mutation leads to significant optic transport defects that are likely to underlie optic atrophy, a major clinical presentation in FDXR patients, as well as a neurodegenerative loss of cells in the central nervous system (CNS). Molecular analysis indicates that FDXR mutation also leads to mitochondrial iron overload and an associated depolarization of the mitochondrial membrane, further supporting the hypothesis that FDXR mutations cause neurodegeneration by affecting FDXR's critical role in iron homeostasis.
线粒体黄素蛋白铁硫蛋白还原酶（FDXR）是铁硫簇生物合成和类固醇生成所必需的。铁硫簇（Fe-S）是普遍存在的辅因子，对各种细胞过程至关重要，越来越多的疾病与 Fe-S 簇合成的中断有关。我们之前的研究表明，FDXR 的功能降低突变会导致人类和小鼠出现一种新型的线粒体病和视神经萎缩，部分原因是电子传递链（ETC）的功能降低以及活性氧（ROS）的产生增加。炎症和周围神经病变也是这种疾病的特征。在本文中，我们证明 FDXR 突变导致显著的视神经运输缺陷，这很可能是 FDXR 患者视神经萎缩的主要临床表现，也是中枢神经系统（CNS）中细胞退行性丧失的基础。分子分析表明，FDXR 突变还导致线粒体铁过载和线粒体膜去极化，这进一步支持了 FDXR 突变通过影响 FDXR 在铁稳态中的关键作用导致神经退行性变的假说。
