Cell-permeable succinate prodrugs bypass mitochondrial complex I deficiency

Nat Commun. 2016 Aug 9;7:12317. doi: 10.1038/ncomms12317.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Membrane Permeability* / drug effects
  • Cell Respiration / drug effects
  • Drug Discovery
  • Drug Evaluation, Preclinical
  • Electron Transport Complex I / deficiency*
  • Electron Transport Complex I / metabolism
  • Electron Transport Complex II / metabolism
  • Fibroblasts / pathology
  • Humans
  • Lactates / metabolism
  • Leigh Disease / pathology
  • Metabolomics
  • Mitochondrial Diseases / metabolism*
  • Models, Biological
  • Prodrugs / chemistry
  • Prodrugs / pharmacology*
  • Succinic Acid / chemistry
  • Succinic Acid / pharmacology*


  • Lactates
  • Prodrugs
  • Succinic Acid
  • Electron Transport Complex II
  • Electron Transport Complex I

Supplementary concepts

  • Mitochondrial complex I deficiency