Children's Hospital of Philadelphia Research Institute, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA.
Mitochondrion. 2011 Mar;11(2):342-50. doi: 10.1016/j.mito.2010.12.003. Epub 2010 Dec 13.
Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by GAA triplet expansions or point mutations in the FXN gene on chromosome 9q13. The gene product called frataxin, a mitochondrial protein that is severely reduced in FRDA patients, leads to mitochondrial iron accumulation, Fe-S cluster deficiency and oxidative damage. The tissue specificity of this mitochondrial disease is complex and poorly understood. While frataxin is ubiquitously expressed, the cellular phenotype is most severe in neurons and cardiomyocytes. Here, we conducted comprehensive proteomic, metabolic and functional studies to determine whether subclinical abnormalities exist in mitochondria of blood cells from FRDA patients. Frataxin protein levels were significantly decreased in platelets and peripheral blood mononuclear cells from FRDA patients. Furthermore, the most significant differences associated with frataxin deficiency in FRDA blood cell mitochondria were the decrease of two mitochondrial heat shock proteins. We did not observe profound changes in frataxin-targeted mitochondrial proteins or mitochondrial functions or an increase of apoptosis in peripheral blood cells, suggesting that functional defects in these mitochondria are not readily apparent under resting conditions in these cells.
弗里德赖希共济失调（FRDA）是一种常染色体隐性神经退行性疾病，由 FXN 基因上 9q13 处的 GAA 三核苷酸重复扩增或点突变引起。该基因产物称为 frataxin，是一种线粒体蛋白，在 FRDA 患者中严重减少，导致线粒体铁积累、Fe-S 簇缺乏和氧化损伤。这种线粒体疾病的组织特异性复杂且了解甚少。虽然 frataxin 广泛表达，但细胞表型在神经元和心肌细胞中最为严重。在这里，我们进行了全面的蛋白质组学、代谢和功能研究，以确定 FRDA 患者血液细胞中的线粒体是否存在亚临床异常。FRDA 患者的血小板和外周血单核细胞中的 frataxin 蛋白水平显著降低。此外，与 FRDA 血液细胞线粒体中 frataxin 缺乏相关的最显著差异是两种线粒体热休克蛋白的减少。我们没有观察到 frataxin 靶向线粒体蛋白或线粒体功能的深刻变化，也没有在外周血细胞中观察到细胞凋亡增加，这表明在这些细胞的静息状态下，这些线粒体的功能缺陷不易察觉。
