Llorens José Vicente, Soriano Sirena, Calap-Quintana Pablo, Gonzalez-Cabo Pilar, Moltó María Dolores
Department of Genetics, Faculty of Biological Sciences, University of Valencia, Valencia, Spain.
Unit for Psychiatry and Neurodegenerative Diseases, Biomedical Research Institute INCLIVA, Valencia, Spain.
Front Neurosci. 2019 Feb 18;13:75. doi: 10.3389/fnins.2019.00075. eCollection 2019.
Friedreich's ataxia (FRDA) is a rare early-onset degenerative disease that affects both the central and peripheral nervous systems, and other extraneural tissues, mainly the heart and endocrine pancreas. This disorder progresses as a mixed sensory and cerebellar ataxia, primarily disturbing the proprioceptive pathways in the spinal cord, peripheral nerves and nuclei of the cerebellum. FRDA is an inherited disease with an autosomal recessive pattern caused by an insufficient amount of the nuclear-encoded mitochondrial protein frataxin, which is an essential and highly evolutionary conserved protein whose deficit results in iron metabolism dysregulation and mitochondrial dysfunction. The first experimental evidence connecting frataxin with iron homeostasis came from ; iron accumulates in the mitochondria of yeast with deletion of the frataxin ortholog gene. This finding was soon linked to previous observations of iron deposits in the hearts of FRDA patients and was later reported in animal models of the disease. Despite advances made in the understanding of FRDA pathophysiology, the role of iron in this disease has not yet been completely clarified. Some of the questions still unresolved include the molecular mechanisms responsible for the iron accumulation and iron-mediated toxicity. Here, we review the contribution of the cellular and animal models of FRDA and relevance of the studies using FRDA patient samples to gain knowledge about these issues. Mechanisms of mitochondrial iron overload are discussed considering the potential roles of frataxin in the major mitochondrial metabolic pathways that use iron. We also analyzed the effect of iron toxicity on neuronal degeneration in FRDA by reactive oxygen species (ROS)-dependent and ROS-independent mechanisms. Finally, therapeutic strategies based on the control of iron toxicity are considered.
弗里德赖希共济失调（FRDA）是一种罕见的早发性退行性疾病，会影响中枢和外周神经系统以及其他神经外组织，主要是心脏和内分泌胰腺。这种疾病以混合性感觉性和小脑性共济失调的形式进展，主要干扰脊髓、外周神经和小脑核中的本体感觉通路。FRDA是一种常染色体隐性遗传疾病，由核编码的线粒体蛋白酵母辅酶A合成酶不足引起，酵母辅酶A合成酶是一种必需且高度进化保守的蛋白质，其缺乏会导致铁代谢失调和线粒体功能障碍。将酵母辅酶A合成酶与铁稳态联系起来的首个实验证据来自；在酵母辅酶A合成酶直系同源基因缺失的酵母线粒体中积累了铁。这一发现很快与之前对FRDA患者心脏中铁沉积的观察结果联系起来，后来在该疾病的动物模型中也有报道。尽管在理解FRDA病理生理学方面取得了进展，但铁在这种疾病中的作用尚未完全阐明。一些仍未解决的问题包括负责铁积累和铁介导毒性的分子机制。在这里，我们回顾了FRDA细胞和动物模型的贡献以及使用FRDA患者样本的研究的相关性，以了解这些问题。考虑到酵母辅酶A合成酶在使用铁的主要线粒体代谢途径中的潜在作用，讨论了线粒体铁过载的机制。我们还通过活性氧（ROS）依赖性和ROS非依赖性机制分析了铁毒性对FRDA神经元变性的影响。最后，考虑了基于控制铁毒性的治疗策略。
