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.
authors: Mitochondrial Medicine, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, BMC A13, 221 84 Lund, Sweden.|NeuroVive Pharmaceutical AB, Medicon Village, 223 81 Lund, Sweden.|Department of Otorhinolaryngology, Head and Neck Surgery, Department of Clinical Sciences Lund, Lund University, Skåne University Hospital, 221 85 Lund, Sweden.
authors: Johannes K
authors: http://orcid.org/0000-0002-2417-5767
authors: JK
authors: Ehinger
authors: Mitochondrial Medicine, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, BMC A13, 221 84 Lund, Sweden.|NeuroVive Pharmaceutical AB, Medicon Village, 223 81 Lund, Sweden.
authors: Sarah
authors: S
authors: Piel
authors: Selcia Ltd, Fyfield Business and Research Park, Fyfield Road, Ongar CM5 0GS, Essex, UK.
authors: Rhonan
authors: R
authors: Ford
authors: Mitochondrial Medicine, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, BMC A13, 221 84 Lund, Sweden.|NeuroVive Pharmaceutical AB, Medicon Village, 223 81 Lund, Sweden.
authors: Michael
authors: M
authors: Karlsson
authors: Mitochondrial Medicine, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, BMC A13, 221 84 Lund, Sweden.|Department of Intensive Care and Perioperative Medicine, Skåne University Hospital, 205 02 Malmö, Sweden.
authors: Fredrik
authors: F
authors: Sjövall
authors: Mitochondrial Medicine, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, BMC A13, 221 84 Lund, Sweden.|NeuroVive Pharmaceutical AB, Medicon Village, 223 81 Lund, Sweden.
authors: Eleonor Åsander
authors: EÅ
authors: Frostner
authors: Mitochondrial Medicine, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, BMC A13, 221 84 Lund, Sweden.
authors: Saori
authors: S
authors: Morota
authors: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: Robert W
authors: RW
authors: Taylor
authors: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: Doug M
authors: DM
authors: Turnbull
authors: Selcia Ltd, Fyfield Business and Research Park, Fyfield Road, Ongar CM5 0GS, Essex, UK.
authors: Clive
authors: C
authors: Cornell
authors: Isomerase Therapeutics Ltd, Chesterford Research Park, Cambridge CB10 1XL, UK.
authors: Steven J
authors: SJ
authors: Moss
authors: Anaesthesiology and Intensive Care, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, 221 85 Lund, Sweden.
authors: Carsten
authors: C
authors: Metzsch
authors: Mitochondrial Medicine, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, BMC A13, 221 84 Lund, Sweden.|NeuroVive Pharmaceutical AB, Medicon Village, 223 81 Lund, Sweden.
authors: Magnus J
authors: MJ
authors: Hansson
authors: Mitopharm Ltd, Fyfield Business and Research Park, Fyfield Road, Ongar CM5 0GS, Essex, UK.
authors: Hans
authors: H
authors: Fliri
authors: Mitochondrial Medicine, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, BMC A13, 221 84 Lund, Sweden.|NeuroVive Pharmaceutical AB, Medicon Village, 223 81 Lund, Sweden.|Clinical Neurophysiology, Department of Clinical Sciences Lund, Lund University, Skåne University Hospital, 221 85 Lund, Sweden.
authors: Eskil
authors: E
authors: Elmér
mesh_terms: D002463:Cell Membrane Permeability / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D042967:Electron Transport Complex I / Q000172:deficiency* / Q000378:metabolism; D042963:Electron Transport Complex II / Q000378:metabolism; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D007773:Lactates / Q000378:metabolism; D007888:Leigh Disease / Q000473:pathology; D055432:Metabolomics; D028361:Mitochondrial Diseases / Q000378:metabolism*; D008954:Models, Biological; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D019802:Succinic Acid / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D007773:Lactates; D011355:Prodrugs; D019802:Succinic Acid; D042963:Electron Transport Complex II; D042967:Electron Transport Complex I