Ehinger 2016 Nat Commun

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Ehinger JK, Piel S, Ford R, Karlsson M, Sjövall F, Frostner EÅ, Morota S, Taylor RW, Turnbull DM, Cornell C, Moss SJ, Metzsch C, Hansson MJ, Fliri H, Elmér E (2016) Cell-permeable succinate prodrugs bypass mitochondrial complex I deficiency. Nat Commun 7:12317.

» PMID: 27502960 Open Access »O2k-brief

Ehinger JK, Piel S, Ford R, Karlsson M, Sjoevall F, Asander FE, Morota S, Taylor RW, Turnbull DM, Cornell C, Moss SJ, Metzsch C, Hansson MJ, Fliri H, Elmer E (2016) Nat Commun

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 [(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.

Keywords: Drug delivery, Energy metabolism, Metabolism

O2k-Network Lab: SE Lund Elmer E



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Labels: MiParea: Respiration, Patients, Pharmacology;toxicology  Pathology: Inherited  Stress:Mitochondrial disease 

Tissue;cell: Heart, Blood cells, Fibroblast  Preparation: Permeabilized tissue, Intact cells  Enzyme: Complex I, Complex II;succinate dehydrogenase  Regulation: Substrate  Coupling state: OXPHOS, ET  Pathway:HRR: Oxygraph-2k 

2016-09, SUIT-010 O2 ce-pce D050, JP, SE, MitoEAGLE blood cells data, O2k-brief