Toggle Main Menu Toggle Search

Open Access padlockePrints

Cell-permeable succinate prodrugs bypass mitochondrial complex I deficiency

Lookup NU author(s): Professor Robert Taylor, Emeritus 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.

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

Date deposited: 08/09/2016

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group


DOI: 10.1038/ncomms12317


Altmetrics provided by Altmetric


Funder referenceFunder name
Crafoord Foundation
Lily Foundation
Linnea and Josef Carlsson foundation
Royal Physiographic Society in Lund
Southern healthcare region, Sweden
Newcastle University Centre for Ageing and Vitality - Biotechnology and Biological Sciences Research Council
Swedish government
UK NHS Specialist Commissioners 'Rare Mitochondrial Disorders of Adults and Children' Service
UK NIHR Biomedical Research Centre in Age and Age Related Diseases award
2011-3470Swedish Research Council
G000608-1MRC Centre for Neuromuscular Disease
G016354/1Newcastle University Centre for Ageing and Vitality - Medical Research Council
G0800674MRC Centre for Translational Research in Neuromuscular Disease Mitochondrial Disease Patient Cohort (UK)
G906919Wellcome Trust Centre for Mitochondrial Research