Research Article: Flavin Adenine Dinucleotide Rescues the Phenotype of Frataxin Deficiency

Date Published: January 25, 2010

Publisher: Public Library of Science

Author(s): Pilar Gonzalez-Cabo, Sheila Ros, Francesc Palau, Antoni L. Andreu.

Abstract: 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.

Partial Text: 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. In addition, most patients show hypertrophic cardiomyopathy. Additional non-neurological features are skeletal deformities and glucose intolerance or diabetes mellitus [1], [2]. The disease is caused by GAA triplet expansions [3] and point mutations [4], [5] in the FXN gene mapped to human chromosome 9q13. FXN encodes frataxin, a small protein of 210 amino acids expressed in the mitochondrial matrix [6]–[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]–[11] and activation of aconitase [12]. Thus, the pathogenic consequences of frataxin deficiency have been related with defects of ISC biogenesis but also with iron deposits [13], oxidative stress [8] and regulation of the mitochondrial respiratory chain [14], [15].

We had previously showed that both yeast and human frataxins interact with complex II subunits Sdh1p/Sdh2p and SDHA/SDHB, respectively [15]. FAD is the prosthetic cofactor of complex II covalently bound to the flavoprotein subunit Sdh1p/SDHA. FAD and FMN are cofactors derived from the metabolism of riboflavin, which has been employed in the treatment of several disorders involving different enzymatic complexes of the OXPHOS system: complex I deficiency [36], [42], [43], complex II deficient patients, at least by reducing the rate of disease progression [40], and in a boy with Leigh syndrome and complex II deficiency [44]. Response to riboflavin in patients with defects of either β-oxidation [45], [46] or single flavo-apoenzymes: pyruvate dehydrogenase [47], electron transfer flavoprotein [48] and short-chain acyl coenzyme A dehydrogenase [37] have been reported as well. Riboflavin has also been used for the treatment of respiratory chain disorders in combination with other cofactors such as nicotinamide in patients with MELAS syndrome, having a favourable response [49].



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