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Cell-permeable succinate prodrugs bypass mitochondrial complex i deficiency

Ehinger, Johannes K. LU orcid ; Piel, Sarah LU orcid ; Ford, Rhonan ; Karlsson, Michael LU ; Sjövall, Fredrik LU orcid ; Frostner, Eleonor Åsander LU ; Morota, Saori LU ; Taylor, Robert W. ; Turnbull, Doug M. and Cornell, Clive , et al. (2016) In Nature Communications 7.
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... (More)

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.

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@article{ab864882-c468-4e5f-b4df-8b3340452240,
  abstract     = {{<p>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.</p>}},
  author       = {{Ehinger, Johannes K. and Piel, Sarah and Ford, Rhonan and Karlsson, Michael and Sjövall, Fredrik and Frostner, Eleonor Åsander and Morota, Saori and Taylor, Robert W. and Turnbull, Doug M. and Cornell, Clive and Moss, Steven J. and Metzsch, Carsten and Hansson, Magnus J. and Fliri, Hans and Elmér, Eskil}},
  issn         = {{2041-1723}},
  keywords     = {{Mitochondria; Complex I; ETS; Complex II; Succinate}},
  language     = {{eng}},
  month        = {{08}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Cell-permeable succinate prodrugs bypass mitochondrial complex i deficiency}},
  url          = {{http://dx.doi.org/10.1038/ncomms12317}},
  doi          = {{10.1038/ncomms12317}},
  volume       = {{7}},
  year         = {{2016}},
}