Cell-permeable succinate prodrugs bypass mitochondrial complex I deficiency.
Nat Commun
; 7: 12317, 2016 08 09.
Article
em En
| MEDLINE
| ID: mdl-27502960
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pró-Fármacos
/
Permeabilidade da Membrana Celular
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Ácido Succínico
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Doenças Mitocondriais
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Complexo I de Transporte de Elétrons
Limite:
Humans
Idioma:
En
Revista:
Nat Commun
Ano de publicação:
2016
Tipo de documento:
Article