Chiang Shannon, Kovacevic Zaklina, Sahni Sumit, Lane Darius J R, Merlot Angelica M, Kalinowski Danuta S, Huang Michael L-H, Richardson Des R
Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia.
Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia
Clin Sci (Lond). 2016 Jun 1;130(11):853-70. doi: 10.1042/CS20160072.
The mitochondrion is a major site for the metabolism of the transition metal, iron, which is necessary for metabolic processes critical for cell vitality. The enigmatic mitochondrial protein, frataxin, is known to play a significant role in both cellular and mitochondrial iron metabolism due to its iron-binding properties and its involvement in iron-sulfur cluster (ISC) and heme synthesis. The inherited neuro- and cardio-degenerative disease, Friedreich's ataxia (FA), is caused by the deficient expression of frataxin that leads to deleterious alterations in iron metabolism. These changes lead to the accumulation of inorganic iron aggregates in the mitochondrial matrix that are presumed to play a key role in the oxidative damage and subsequent degenerative features of this disease. Furthermore, the concurrent dys-regulation of cellular antioxidant defense, which coincides with frataxin deficiency, exacerbates oxidative stress. Hence, the pathogenesis of FA underscores the importance of the integrated homeostasis of cellular iron metabolism and the cytoplasmic and mitochondrial redox environments. This review focuses on describing the pathogenesis of the disease, the molecular mechanisms involved in mitochondrial iron-loading and the dys-regulation of cellular antioxidant defense due to frataxin deficiency. In turn, current and emerging therapeutic strategies are also discussed.
线粒体是过渡金属铁代谢的主要场所，铁对于维持细胞活力至关重要的代谢过程必不可少。神秘的线粒体蛋白——共济失调蛋白，因其具有铁结合特性且参与铁硫簇（ISC）和血红素合成，在细胞和线粒体铁代谢中发挥着重要作用。遗传性神经和心脏退行性疾病——弗里德赖希共济失调（FA），是由共济失调蛋白表达不足导致铁代谢有害改变引起的。这些变化导致线粒体基质中无机铁聚集体的积累，推测其在该疾病的氧化损伤及后续退行性特征中起关键作用。此外，与共济失调蛋白缺乏同时出现的细胞抗氧化防御失调，会加剧氧化应激。因此，FA的发病机制凸显了细胞铁代谢以及细胞质和线粒体氧化还原环境整体稳态的重要性。本综述着重描述该疾病的发病机制、线粒体铁过载所涉及的分子机制以及由于共济失调蛋白缺乏导致的细胞抗氧化防御失调。相应地，还讨论了当前和新兴的治疗策略。
