Affiliations: [a] Wellcome Trust Mitochondrial Research Centre and the John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, UK
| [b] Present address: Department of Clinical Neurosciences, Cambridge and MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK
Newcastle Eye Centre, Royal Victoria Infirmary, Newcastle upon Tyne, UK
NIHR Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology, London, UK
Correspondence to: Rita Horvath MD, PhD, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK. Tel.: +44 191 2418855; Fax: +44 191 2418666; E-mail: Rita.Horvath@ncl.ac.uk.
Note:  MB and JSM contributed equally to this study.
Abstract: Background: Mitochondrial encephalomyopathies are severe, relentlessly progressive conditions and there are very few effective therapies available to date. We have previously suggested that in two rare forms of reversible mitochondrial disease (reversible infantile respiratory chain deficiency and reversible infantile hepatopathy) supplementation with L-cysteine can improve mitochondrial protein synthesis, since cysteine is required for the 2-thiomodification of mitochondrial tRNAs. Objectives: We studied whether supplementation with L-cysteine or N-acetyl-cysteine (NAC) results in any improvement of the mitochondrial function in vitro in fibroblasts of patients with different genetic forms of abnormal mitochondrial translation. Methods: We studied in vitro in fibroblasts of patients carrying the common m.3243A>G and m.8344A>G mutations or autosomal recessive mutations in genes affecting mitochondrial translation, whether L-cysteine or N-acetyl-cysteine supplementation have an effect on mitochondrial respiratory chain function. Results: Here we show that supplementation with L-cysteine, but not with N-acetyl-cysteine partially rescues the mitochondrial translation defect in vitro in fibroblasts of patients carrying the m.3243A>G and m.8344A>G mutations. In contrast, N-acetyl-cysteine had a beneficial effect on mitochondrial translation in TRMU and MTO1 deficient fibroblasts. Conclusions: Our results suggest that L-cysteine or N-acetyl-cysteine supplementation may be a potential treatment for selected subgroups of patients with mitochondrial translation deficiencies. Further studies are needed to explore the full potential of cysteine supplementation as a treatment for patients with mitochondrial disease.