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Cell-permeable succinate prodrugs bypass mitochondrial complex I deficiency

Lookup NU author(s): Professor Robert Taylor, Professor Doug Turnbull

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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 metabolism of [C-13]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 metadata

Author(s): Ehinger JK, Piel S, Ford R, Karlsson M, Sjovall F, Frostner EA, Morota S, Taylor RW, Turnbull DM, Cornell C, Moss SJ, Metzsch C, Hansson MJ, Fliri H, Elmer E

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2016

Volume: 7

Online publication date: 09/08/2016

Acceptance date: 21/06/2016

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/ncomms12317

DOI: 10.1038/ncomms12317


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