Lookup NU author(s): Professor Robert Taylor,
Professor Doug Turnbull
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
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
Online publication date: 09/08/2016
Acceptance date: 21/06/2016
ISSN (electronic): 2041-1723
Publisher: Nature Publishing Group
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