Metabolic consequences of mitochondrial coenzyme A deficiency in patients with PANK2 mutations
Metabolic consequences of mitochondrial coenzyme A deficiency in patients with PANK2 mutations
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DOI：
10.1016/j.ymgme.2011.12.005
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发表时间：
2012-03-01
影响因子：
3.8
通讯作者：
Tiranti, Valeria
中科院分区：
文献类型：
--
作者：
Leoni, Valerio;Strittmatter, Laura;Tiranti, Valeria
泛酸激酶相关神经退行性变(PKAN)是一种罕见的先天性代谢错误，其特征是铁在基底节积聚，并存在肌张力障碍、构音障碍和视网膜变性。泛酸激酶2(PANK2)是线粒体辅酶A生物合成中的限速酶，它的突变是导致这种疾病的最常见的遗传原因。这种核心代谢酶的突变是如何导致如此广泛的临床病理谱仍是一个谜。为了系统地探索其发病机制，我们对14名遗传定义的患者和18名对照的血浆进行了全球代谢谱分析。值得注意的是，PKAN患者的乳酸升高，提示线粒体代谢功能障碍。正如预测的那样，但以前从未报道过，在PANK2过早停止突变的患者中，泛酸水平更高。对患者来源的成纤维细胞的全球代谢概况和后续研究还发现，胆汁酸结合和脂代谢存在缺陷，这是需要辅酶A的途径。这些发现提出了一个新的治疗假说，即膳食脂肪和胆汁酸补充剂可能具有作为疾病修改干预措施的潜力。我们的研究说明了代谢图谱作为系统探索遗传性代谢性疾病的生化基础的工具的价值。(C)2011 Elsevier Inc.保留所有权利。
Pantothenate kinase-associated neurodegeneration (PKAN) is a rare, inborn error of metabolism characterized by iron accumulation in the basal ganglia and by the presence of dystonia, dysarthria, and retinal degeneration. Mutations in pantothenate kinase 2 (PANK2), the rate-limiting enzyme in mitochondrial coenzyme A biosynthesis, represent the most common genetic cause of this disorder. How mutations in this core metabolic enzyme give rise to such a broad clinical spectrum of pathology remains a mystery. To systematically explore its pathogenesis, we performed global metabolic profiling on plasma from a cohort of 14 genetically defined patients and 18 controls. Notably, lactate is elevated in PKAN patients, suggesting dysfunctional mitochondria] metabolism. As predicted, but never previously reported, pantothenate levels are higher in patients with premature stop mutations in PANK2. Global metabolic profiling and follow-up studies in patient-derived fibroblasts also reveal defects in bile acid conjugation and lipid metabolism, pathways that require coenzyme A. These findings raise a novel therapeutic hypothesis, namely, that dietary fats and bile acid supplements may hold potential as disease-modifying interventions. Our study illustrates the value of metabolic profiling as a tool for systematically exploring the biochemical basis of inherited metabolic diseases. (C) 2011 Elsevier Inc. All rights reserved.