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Cell-permeable succ...
Cell-permeable succinate prodrugs bypass mitochondrial complex i deficiency
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- Ehinger, Johannes K. (author)
- Lund University,Lunds universitet,Mitokondriell Medicin,Forskargrupper vid Lunds universitet,Mitochondrial Medicine,Lund University Research Groups,Skåne University Hospital,NeuroVive Pharmaceutical AB
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- Piel, Sarah (author)
- Lund University,Lunds universitet,Mitokondriell Medicin,Forskargrupper vid Lunds universitet,Mitochondrial Medicine,Lund University Research Groups,NeuroVive Pharmaceutical AB
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- Ford, Rhonan (author)
- Selcia Ltd.
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- Karlsson, Michael (author)
- Lund University,Lunds universitet,Mitokondriell Medicin,Forskargrupper vid Lunds universitet,Mitochondrial Medicine,Lund University Research Groups,NeuroVive Pharmaceutical AB
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- Sjövall, Fredrik (author)
- Lund University,Lunds universitet,Mitokondriell Medicin,Forskargrupper vid Lunds universitet,Mitochondrial Medicine,Lund University Research Groups,Skåne University Hospital
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- Frostner, Eleonor Åsander (author)
- Lund University,Lunds universitet,Mitokondriell Medicin,Forskargrupper vid Lunds universitet,Mitochondrial Medicine,Lund University Research Groups,NeuroVive Pharmaceutical AB
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- Morota, Saori (author)
- Lund University,Lunds universitet,Mitokondriell Medicin,Forskargrupper vid Lunds universitet,Mitochondrial Medicine,Lund University Research Groups
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- Taylor, Robert W. (author)
- University of Newcastle upon Tyne
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- Turnbull, Doug M. (author)
- University of Newcastle upon Tyne
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- Cornell, Clive (author)
- Selcia Ltd.
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- Moss, Steven J. (author)
- Isomerase Therapeutics Ltd.
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- Metzsch, Carsten (author)
- Lund University,Lunds universitet,Anestesiologi och intensivvård,Forskargrupper vid Lunds universitet,Anaesthesiology and Intensive Care Medicine,Lund University Research Groups
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- Hansson, Magnus J. (author)
- Lund University,Lunds universitet,Mitokondriell Medicin,Forskargrupper vid Lunds universitet,Mitochondrial Medicine,Lund University Research Groups,NeuroVive Pharmaceutical AB
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- Fliri, Hans (author)
- Mitopharm Ltd
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- Elmér, Eskil (author)
- Lund University,Lunds universitet,Klinisk neurofysiologi,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Clinical Neurophysiology,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine
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(creator_code:org_t)
- 2016-08-09
- 2016
- English.
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
- Related links:
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http://dx.doi.org/10... (free)
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Pediatrik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Pediatrics (hsv//eng)
Keyword
- Mitochondria
- Complex I
- ETS
- Complex II
- Succinate
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Ehinger, Johanne ...
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Piel, Sarah
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Ford, Rhonan
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Karlsson, Michae ...
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Sjövall, Fredrik
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Frostner, Eleono ...
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show more...
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Morota, Saori
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Taylor, Robert W ...
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Turnbull, Doug M ...
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Cornell, Clive
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Moss, Steven J.
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Metzsch, Carsten
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Hansson, Magnus ...
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Fliri, Hans
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Elmér, Eskil
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Neurology
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Pharmaceutical S ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Pediatrics
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Nature Communica ...
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Lund University