Cell-permeable succinate prodrugs bypass mitochondrial complex I deficiency

Johannes K. Ehinger (), Sarah Piel, Rhonan Ford, Michael Karlsson, Fredrik Sjövall, Eleonor Åsander Frostner, Saori Morota, Robert W. Taylor, Doug M. Turnbull, Clive Cornell, Steven J. Moss, Carsten Metzsch, Magnus J. Hansson, Hans Fliri and Eskil Elmér
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Johannes K. Ehinger: Mitochondrial Medicine, Faculty of Medicine, Lund University, BMC A13, 221 84 Lund, Sweden
Sarah Piel: Mitochondrial Medicine, Faculty of Medicine, Lund University, BMC A13, 221 84 Lund, Sweden
Rhonan Ford: Selcia Ltd, Fyfield Business and Research Park
Michael Karlsson: Mitochondrial Medicine, Faculty of Medicine, Lund University, BMC A13, 221 84 Lund, Sweden
Fredrik Sjövall: Mitochondrial Medicine, Faculty of Medicine, Lund University, BMC A13, 221 84 Lund, Sweden
Eleonor Åsander Frostner: Mitochondrial Medicine, Faculty of Medicine, Lund University, BMC A13, 221 84 Lund, Sweden
Saori Morota: Mitochondrial Medicine, Faculty of Medicine, Lund University, BMC A13, 221 84 Lund, Sweden
Robert W. Taylor: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University
Doug M. Turnbull: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University
Clive Cornell: Selcia Ltd, Fyfield Business and Research Park
Steven J. Moss: Isomerase Therapeutics Ltd, Chesterford Research Park
Carsten Metzsch: Anaesthesiology and Intensive Care, Faculty of Medicine, Lund University
Magnus J. Hansson: Mitochondrial Medicine, Faculty of Medicine, Lund University, BMC A13, 221 84 Lund, Sweden
Hans Fliri: Mitopharm Ltd, Fyfield Business and Research Park
Eskil Elmér: Mitochondrial Medicine, Faculty of Medicine, Lund University, BMC A13, 221 84 Lund, Sweden

Nature Communications, 2016, vol. 7, issue 1, 1-8

Abstract: 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 [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.

Date: 2016
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DOI: 10.1038/ncomms12317

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