The phylogenetic distribution of frataxin indicates a role in iron-sulfur cluster protein assembly

Much has been learned about the cellular pathology of Friedreich's ataxia, a recessive neurodegenerative disease resulting from insufficient expressio n of the mitochondrial protein frataxin. However, the biochemical function of frataxin has remained obscure, hampering attempts at therapeutic interve ntion. To predict functional interactions of frataxin with other proteins w e investigated whether its gene specifically co-occurs with any other genes in sequenced genomes. In 56 available genomes we identified two genes with identical phylogenetic distributions to the frataxin/cyaY gene: hscA and h scB/JAC1. These genes have not only emerged in the same evolutionary lineag e as the frataxin gene, they have also been lost at least twice with it, an d they have been horizontally transferred with it in the evolution of the m itochondria. The proteins encoded by hscA and hscB, the chaperone HSP66 and the co-chaperone HSP20, have been shown to be required for the synthesis o f 2Fe-2S clusters on ferredoxin in proteobacteria. JAC1, an ortholog of hsc B, and SSQ1, a paralog of hscA, have been shown to be required for iron-sul fur cluster assembly in mitochondria of Saccharomyces cerevisiae. Combining data on the co-occurrence of genes in genomes with experimental and predic ted cellular localization data of their proteins supports the hypothesis th at frataxin is directly involved in iron-sulfur cluster protein assembly. T hey indicate that frataxin is specifically involved in the same sub-process as HSP20/Jac1p.