Cell-permeable succinate prodrugs bypass mitochondrial complex I deficiency.
Cell-permeable succinate prodrugs bypass mitochondrial complex I deficiency.
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DOI：
10.1038/ncomms12317
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发表时间：
2016-08-09
影响因子：
16.6
通讯作者：
Elmér E
中科院分区：
文献类型：
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作者：
Ehinger JK;Piel S;Ford R;Karlsson M;Sjövall F;Frostner EÅ;Morota S;Taylor RW;Turnbull DM;Cornell C;Moss SJ;Metzsch C;Hansson MJ;Fliri H;Elmér E
线粒体复合物I（CI）缺陷是儿科线粒体疾病中呼吸链中最常见的缺陷。这组异质性疾病包括严重或致命的神经系统表现，如Leigh综合征，现有循证治疗方案非常有限。在这里，我们描述了复合物II底物琥珀酸盐的细胞膜可渗透的前药增加CI缺陷的人血细胞、成纤维细胞和心脏纤维中的ATP连接的线粒体呼吸。由于鱼藤酮诱导的CI抑制导致的血小板中乳酸盐积累被逆转，并且鱼藤酮诱导的白色血细胞中乳酸盐：丙酮酸盐比率的增加被减轻。代谢组学分析证明了[13 C]琥珀酸盐的递送和代谢。在Leigh综合征患者成纤维细胞中，具有隐性NDUFS2突变，呼吸和备用呼吸能力通过前药给药增加。我们的结论是，前药递送的琥珀酸绕过CI并支持电子传递、膜电位和ATP产生。该策略为由于线粒体CI功能障碍导致的代谢失代偿提供了潜在的未来疗法。 线粒体复合物I缺乏症是儿童线粒体疾病中最常见的呼吸链缺陷，目前尚无有效的治疗方法。在这项研究中，作者表明琥珀酸酯前药可以减轻Leigh综合征患者成纤维细胞的代谢失代偿。
Mitochondrial complex I (CI) deficiency is the most prevalent defect in the respiratory chain in paediatric mitochondrial disease. This heterogeneous group of diseases includes serious or fatal neurological presentations such as Leigh syndrome and there are very limited evidence-based treatment options available. Here we describe that cell membrane-permeable prodrugs of the complex II substrate succinate increase ATP-linked mitochondrial respiration in CI-deficient human blood cells, fibroblasts and heart fibres. Lactate accumulation in platelets due to rotenone-induced CI inhibition is reversed and rotenone-induced increase in lactate:pyruvate ratio in white blood cells is alleviated. Metabolomic analyses demonstrate delivery and metabolism of [13C]succinate. In Leigh syndrome patient fibroblasts, with a recessive NDUFS2 mutation, respiration and spare respiratory capacity are increased by prodrug administration. We conclude that prodrug-delivered succinate bypasses CI and supports electron transport, membrane potential and ATP production. This strategy offers a potential future therapy for metabolic decompensation due to mitochondrial CI dysfunction. Mitochondrial complex I deficiency is the most common respiratory chain defect in mitochondrial disease in children and currently there is no effective treatment. In this study, the authors show that succinate prodrugs can alleviate metabolic decompensation in Leigh syndrome patient fibroblasts.