Marina Bartsakoulia1, Juliane S Mϋller1, Aurora Gomez-Duran1,2, Patrick Yu-Wai-Man1,3,4, Veronika Boczonadi1, Rita Horvath1. 1. 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. 2. Present address: Department of Clinical Neurosciences, Cambridge and MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK. 3. Newcastle Eye Centre, Royal Victoria Infirmary, Newcastle upon Tyne, UK. 4. NIHR Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology, London, UK.
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.
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.
Authors: Stephen F Kingsmore; Audrey Henderson; Mallory J Owen; Michelle M Clark; Christian Hansen; David Dimmock; Christina D Chambers; Laura L Jeliffe-Pawlowski; Charlotte Hobbs Journal: NPJ Genom Med Date: 2020-11-02 Impact factor: 8.617
Authors: Chaya N Murali; Claudia Soler-Alfonso; Kathleen M Loomes; Amit A Shah; Danielle Monteil; Carmencita D Padilla; Fernando Scaglia; Rebecca Ganetzky Journal: Mol Genet Metab Date: 2021-01-14 Impact factor: 4.797
Authors: James J O'Byrne; Maja Tarailo-Graovac; Aisha Ghani; Michael Champion; Charu Deshpande; Ali Dursun; Riza K Ozgul; Peter Freisinger; Ian Garber; Tobias B Haack; Rita Horvath; Ivo Barić; Ralf A Husain; Leo A J Kluijtmans; Urania Kotzaeridou; Andrew A Morris; Colin J Ross; Saikat Santra; Jan Smeitink; Mark Tarnopolsky; Saskia B Wortmann; Johannes A Mayr; Michaela Brunner-Krainz; Holger Prokisch; Wyeth W Wasserman; Ron A Wevers; Udo F Engelke; Richard J Rodenburg; Teck Wah Ting; Robert McFarland; Robert W Taylor; Ramona Salvarinova; Clara D M van Karnebeek Journal: Mol Genet Metab Date: 2017-11-15 Impact factor: 4.797
Authors: Stephen F Kingsmore; Audrey Henderson; Mallory J Owen; Michelle M Clark; Christian Hansen; David Dimmock; Christina D Chambers; Laura L Jeliffe-Pawlowski; Charlotte Hobbs Journal: NPJ Genom Med Date: 2020-11-02 Impact factor: 8.617