Department of Otolaryngology-Head & Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, United States of America; Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, United States of America; Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, United States of America.
Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, United States of America; Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, United States of America.
Mol Genet Metab. 2022 Aug;136(4):306-314. doi: 10.1016/j.ymgme.2022.06.002. Epub 2022 Jun 13.
Friedreich Ataxia (FA) is a rare and often fatal autosomal recessive disease in which a mitochondrial protein, frataxin (FXN), is severely reduced in all tissues. With loss of FXN, mitochondrial metabolism is severely disrupted. Multiple therapeutic approaches are in development, but a key limitation is the lack of biomarkers reflecting the activity of FXN in a timely fashion. We predicted this dysregulated metabolism would present a unique metabolite profile in blood of FA patients versus Controls (Con). Plasma from 10 FA and 11 age and sex matched Con subjects was analyzed by targeted mass spectrometry and untargeted NMR. This combined approach yielded quantitative measurements for 540 metabolites and found 59 unique metabolites (55 from MS and 4 from NMR) that were significantly different between cohorts. Correlation-based network analysis revealed several clusters of pathway related metabolites including a cluster associated with one‑carbon (1C) metabolism composed of formate, sarcosine, hypoxanthine, and homocysteine. Receiver operator characteristics analyses demonstrated an excellent ability to discriminate between Con and FA with AUC values >0.95. These results are the first reported metabolomic analyses of human patients with FA. The metabolic perturbations, especially those related to 1C metabolism, may serve as a valuable biomarker panel of disease progression and response to therapy. The identification of dysregulated 1C metabolism may also inform the search for new therapeutic targets related to this pathway.
弗里德赖希共济失调（FA）是一种罕见的常染色体隐性遗传病，所有组织中都严重缺乏线粒体蛋白 frataxin（FXN）。随着 FXN 的缺失，线粒体代谢严重紊乱。目前正在开发多种治疗方法，但一个关键的限制是缺乏及时反映 FXN 活性的生物标志物。我们预测这种失调的代谢会在 FA 患者与对照（Con）的血液中呈现出独特的代谢物谱。通过靶向质谱和非靶向 NMR 分析了 10 名 FA 和 11 名年龄和性别匹配的 Con 受试者的血浆。这种联合方法为 540 种代谢物提供了定量测量值，并发现了 59 种独特的代谢物（55 种来自 MS，4 种来自 NMR），它们在队列之间存在显著差异。基于相关性的网络分析揭示了几个与代谢途径相关的代谢物簇，包括与一碳（1C）代谢相关的簇，由甲酸、肌氨酸、次黄嘌呤和同型半胱氨酸组成。接收者操作特性分析表明，区分 Con 和 FA 的能力非常出色，AUC 值>0.95。这些结果是首次对人类 FA 患者进行的代谢组学分析。代谢紊乱，特别是与 1C 代谢相关的紊乱，可能作为疾病进展和治疗反应的有价值的生物标志物组。失调的 1C 代谢的鉴定也可能为寻找与该途径相关的新治疗靶点提供信息。
