Abstract
BackgroundFriedreich 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.Methods and FindingsHere 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 yfh1Δ 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/SignificanceWe 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.
Highlights
Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder characterized by early onset and progressive limb and gait ataxia, dysarthria, deep tendon areflexia especially of the lower extremities, and presence of a sensory axonal neuropathy with motor conduction velocities greater than 40 m/s
We had previously showed that both yeast and human frataxins interact with complex II subunits Sdh1p/Sdh2p and SDHA/ SDHB, respectively [15]
flavin adenine dinucleotide (FAD) is the prosthetic cofactor of complex II covalently bound to the flavoprotein subunit Sdh1p/ SDHA
Summary
Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder characterized by early onset and progressive limb and gait ataxia, dysarthria, deep tendon areflexia especially of the lower extremities, and presence of a sensory axonal neuropathy with motor conduction velocities greater than 40 m/s. Additional non-neurological features are skeletal deformities and glucose intolerance or diabetes mellitus [1,2]. FXN encodes frataxin, a small protein of 210 amino acids expressed in the mitochondrial matrix [6,7,8]. Frataxin seems to act as a iron donor to other proteins for their utilization in different biochemical pathways, such as biogenesis of iron-sulfur clusters (ISC) [9,10,11] and activation of aconitase [12]. The pathogenic consequences of frataxin deficiency have been related with defects of ISC biogenesis and with iron deposits [13], oxidative stress [8] and regulation of the mitochondrial respiratory chain [14,15]. 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
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