Cell-permeable succinate prodrugs bypass mitochondrial complex i deficiency

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Cell-permeable succinate prodrugs bypass mitochondrial complex i deficiency. / Ehinger, Johannes K.; Piel, Sarah; Ford, Rhonan; Karlsson, Michael; Sjövall, Fredrik; Frostner, Eleonor Åsander; Morota, Saori; Taylor, Robert W.; Turnbull, Doug M.; Cornell, Clive; Moss, Steven J.; Metzsch, Carsten; Hansson, Magnus J.; Fliri, Hans; Elmér, Eskil.

In: Nature Communications, Vol. 7, 12317, 09.08.2016.

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Ehinger, Johannes K. ; Piel, Sarah ; Ford, Rhonan ; Karlsson, Michael ; Sjövall, Fredrik ; Frostner, Eleonor Åsander ; Morota, Saori ; Taylor, Robert W. ; Turnbull, Doug M. ; Cornell, Clive ; Moss, Steven J. ; Metzsch, Carsten ; Hansson, Magnus J. ; Fliri, Hans ; Elmér, Eskil. / Cell-permeable succinate prodrugs bypass mitochondrial complex i deficiency. In: Nature Communications. 2016 ; Vol. 7.

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TY - JOUR

T1 - Cell-permeable succinate prodrugs bypass mitochondrial complex i deficiency

AU - Ehinger, Johannes K.

AU - Piel, Sarah

AU - Ford, Rhonan

AU - Karlsson, Michael

AU - Sjövall, Fredrik

AU - Frostner, Eleonor Åsander

AU - Morota, Saori

AU - Taylor, Robert W.

AU - Turnbull, Doug M.

AU - Cornell, Clive

AU - Moss, Steven J.

AU - Metzsch, Carsten

AU - Hansson, Magnus J.

AU - Fliri, Hans

AU - Elmér, Eskil

PY - 2016/8/9

Y1 - 2016/8/9

N2 - 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.

AB - 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.

KW - Mitochondria

KW - Complex I

KW - ETS

KW - Complex II

KW - Succinate

UR - http://www.scopus.com/inward/record.url?scp=84982103042&partnerID=8YFLogxK

U2 - 10.1038/ncomms12317

DO - 10.1038/ncomms12317

M3 - Article

C2 - 27502960

AN - SCOPUS:84982103042

VL - 7

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 12317

ER -