Cell-permeable succinate prodrugs bypass mitochondrial complex i deficiency

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title = "Cell-permeable succinate prodrugs bypass mitochondrial complex i deficiency",
abstract = "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 [ 13 C]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.",
keywords = "Mitochondria, Complex I, ETS, Complex II, Succinate",
author = "Ehinger, {Johannes K.} and Sarah Piel and Rhonan Ford and Michael Karlsson and Fredrik Sj{\"o}vall and Frostner, {Eleonor {\AA}sander} and Saori Morota and Taylor, {Robert W.} and Turnbull, {Doug M.} and Clive Cornell and Moss, {Steven J.} and Carsten Metzsch and Hansson, {Magnus J.} and Hans Fliri and Eskil Elm{\'e}r",
year = "2016",
month = aug,
day = "9",
doi = "10.1038/ncomms12317",
language = "English",
volume = "7",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",