Low-concentration methylene blue maintains energy production and strongly improves survival of Leigh syndrome French Canadian skin fibroblasts.
Leigh syndrome French Canadian (LSFC) is a recessive disease caused by mutations in the LRPPRC gene (leucine-rich pentatricopeptide repeat containing protein). These mutations induce a cytochrome c oxidase (COX) deficiency resulting in episodes of acute acidotic crisis that will often lead to death. There is no effective treatment. Methylene blue (MB) is a redox dye that increases COX content and activity in vitro and in vivo suggesting that MB could prevent and treat LSFC. In this study, the protective effect of low-concentration MB was tested on two LSFC cell lines, including LSFC-F1, homozygous for the mutation A354V, and LSFC-F2 a compound heterozygous for the mutations A354V and C12775STOP. MB effect on metabolic activity was assessed on both LSFC cells in stable and acidotic conditions. For LSFC-F1, results showed that metabolic activity drastically decline after 96 hours in both conditions but not LSFC-F2 and normal cells. MB completely prevents the decrease of metabolic activity in LSFC-F1. Intracellular ATP content was also measured in both culture media. After 96 hours in acidotic medium, ATP content was almost completely depleted for both LSFC cells. Interestingly, MB completely restores ATP content in LSFC-F1 and LSFC-F2 cells. Finally, MB strongly improves the survival of both LSFC cells.
Department of Fundamental Sciences, Université du Québec à Chicoutimi, 555 Boulevard de l'Université, Chicoutimi, Québec, Canada. Jean_Legault@uqac.ca
Jean
J
Legault
Pierre-Luc
PL
Larouche
Isabelle
I
Côté
Line
L
Bouchard
André
A
Pichette
Brian H
BH
Robinson
Charles
C
Morin
D000255:Adenosine Triphosphate / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D030401:Cytochrome-c Oxidase Deficiency / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D003576:Electron Transport Complex IV / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007888:Leigh Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008751:Methylene Blue / Q000494:pharmacology*; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
C087940:LRPPRC protein, human; D009363:Neoplasm Proteins; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; D008751:Methylene Blue