Cell-permeable succinate prodrugs bypass mitochondrial complex i deficiency

Johannes K. Ehinger, Sarah Piel, Rhonan Ford, Michael Karlsson, Fredrik Sjövall, Eleonor Åsander Frostner, Saori Morota, Robert W. Taylor, Doug M. Turnbull, Clive Cornell, Steven J. Moss, Carsten Metzsch, Magnus J. Hansson, Hans Fliri, Eskil Elmér

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskriftPeer review

Sammanfattning

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.

Originalspråkengelska
Artikelnummer12317
TidskriftNature Communications
Volym7
DOI
StatusPublished - 2016 aug. 9

Ämnesklassifikation (UKÄ)

  • Neurologi
  • Farmaceutiska vetenskaper
  • Pediatrik

Fingeravtryck

Utforska forskningsämnen för ”Cell-permeable succinate prodrugs bypass mitochondrial complex i deficiency”. Tillsammans bildar de ett unikt fingeravtryck.

Citera det här