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Cell-permeable succinate prodrugs bypass mitochondrial complex i deficiency

Ehinger, Johannes K. LU ; Piel, Sarah LU ; Ford, Rhonan; Karlsson, Michael LU ; Sjövall, Fredrik LU ; 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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published
subject
keywords
Mitochondria, Complex I, ETS, Complex II, Succinate
in
Nature Communications
volume
7
publisher
Nature Publishing Group
external identifiers
  • scopus:84982103042
  • wos:000380951900001
ISSN
2041-1723
DOI
10.1038/ncomms12317
language
English
LU publication?
yes
id
ab864882-c468-4e5f-b4df-8b3340452240
date added to LUP
2016-08-29 12:41:38
date last changed
2017-08-01 13:15:33
@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>},
  articleno    = {12317},
  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},
  keyword      = {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},
  volume       = {7},
  year         = {2016},
}