A Metabolic Signature of Mitochondrial Dysfunction Revealed through a Monogenic Form of Leigh Syndrome.
A Metabolic Signature of Mitochondrial Dysfunction Revealed through a Monogenic Form of Leigh Syndrome.
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DOI：
10.1016/j.celrep.2015.09.054
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发表时间：
2015-11-03
期刊：
影响因子：
8.8
通讯作者：
Des Rosiers C
中科院分区：
文献类型：
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作者：
Thompson Legault J;Strittmatter L;Tardif J;Sharma R;Tremblay-Vaillancourt V;Aubut C;Boucher G;Clish CB;Cyr D;Daneault C;Waters PJ;LSFC Consortium;Vachon L;Morin C;Laprise C;Rioux JD;Mootha VK;Des Rosiers C
线粒体呼吸的下降是大量先天性代谢缺陷的根本原因。它还与常见的与年龄相关的疾病和衰老过程有关。为了深入了解呼吸链功能障碍的全身生化后果，我们在遗传同质的加拿大法利氏综合征患者队列中进行了一项病例对照、前瞻性代谢分析研究，该综合征是一种由于 LRPPRC 功能丧失突变导致的线粒体呼吸链疾病。我们发现了 45 种血浆和尿液分析物，可区分患者和对照组，包括线粒体代谢功能障碍的经典标志物（乳酸和酰基肉碱），以及心脏代谢风险的意外标志物（胰岛素和脂联素）、与 NADH 状态相关的氨基酸分解代谢（α-羟基丁酸）和 NAD+ 生物合成（犬尿氨酸和 3-羟基邻氨基苯甲酸）。我们的研究确定了可能位于原发性线粒体病变下游的系统性代谢途径紊乱，这对于了解细胞器如何导致罕见和常见疾病具有重要意义。
A decline in mitochondrial respiration represents the root cause of a large number of inborn errors of metabolism. It is also associated with common age-associated diseases and the aging process. To gain insight into the systemic, biochemical consequences of respiratory chain dysfunction, we performed a case-control, prospective metabolic profiling study in a genetically homogenous cohort of patients with Leigh syndrome French Canadian variant, a mitochondrial respiratory chain disease due to loss-of-function mutations in LRPPRC. We discovered 45 plasma and urinary analytes discriminating patients from controls, including classic markers of mitochondrial metabolic dysfunction (lactate and acylcarnitines), as well as unexpected markers of cardiometabolic risk (insulin and adiponectin), amino acid catabolism linked to NADH status (α-hydroxybutyrate), and NAD+ biosynthesis (kynurenine and 3-hydroxyanthranilic acid). Our study identifies systemic, metabolic pathway derangements that can lie downstream of primary mitochondrial lesions, with implications for understanding how the organelle contributes to rare and common diseases.