Flavin adenine dinucleotide rescues the phenotype of frataxin deficiency.
BACKGROUND
Friedreich ataxia is a neurodegenerative disease caused by the lack of frataxin, a mitochondrial protein. We previously demonstrated that frataxin interacts with complex II subunits of the electronic transport chain (ETC) and putative electronic transfer flavoproteins, suggesting that frataxin could participate in the oxidative phosphorylation.


RESULTS
Here we have investigated the effect of riboflavin and its cofactors flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) in Saccharomyces cerevisiae and Caenorhabditis elegans models of frataxin deficiency. We used a S. cerevisiae strain deleted for the yfh1 gene obtained by homologous recombination and we assessed growth in fermentable and non-fermentable cultures supplemented with either riboflavin or its derivates. Experiments with C. elegans were performed in transient knock-down worms (frh-1[RNAi]) generated by microinjection of dsRNA frh-1 into the gonads of young worms. We observed that FAD rescues the phenotype of both defective organisms. We show that cell growth and enzymatic activities of the ETC complexes and ATP production of yfh1Delta cells were improved by FAD supplementation. Moreover, FAD also improved lifespan and other physiological parameters in the C. elegans knock-down model for frataxin.


CONCLUSIONS
We propose that rescue of frataxin deficiency by FAD supplementation could be explained by an improvement in mitochondrial respiration. We suggest that riboflavin may be useful in the treatment of Friedreich ataxia.
Gonzalez-Cabo
Pilar
P
Laboratory of Genetics and Molecular Medicine, Instituto de Biomedicina de Valencia, CSIC, Valencia, Spain.
Ros
Sheila
S
Palau
Francesc
F
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005182:Flavin-Adenine Dinucleotide / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D033862:Iron-Binding Proteins / Q000235:genetics*; D008954:Models, Biological; D010085:Oxidative Phosphorylation; D010641:Phenotype; D011995:Recombination, Genetic; D012441:Saccharomyces cerevisiae / Q000235:genetics; D000096923:Frataxin
D000255:Adenosine Triphosphate; D005182:Flavin-Adenine Dinucleotide; D033862:Iron-Binding Proteins; D000096923:Frataxin