Yoon H, Golla R, Lesuisse E, Pain J, Donald J, Lyver ER, Pain D, Dancis A

Frataxin is a conserved mitochondrial protein deficient in patients with Friedreich's ataxia. Frataxin has been implicated in control of iron homeostasis and Fe-S cluster assembly. In yeast or human mitochondria, frataxin interacts with components of the Fe-S cluster synthesis machinery, including the cysteine desulfurase (Nfs1), accessory protein (Isd11), and scaffold ...

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protein (Isu). Here we report that a single amino acid substitution (methionine to isoleucine) at position 107 in the mature form of Isu1 protein restored many deficient functions in ∆yfh1 or frataxin-depleted yeast cells. Iron homeostasis was improved such that soluble/usable mitochondrial iron was increased and accumulation of insoluble/non-usable iron within mitochondria was largely prevented. Cytochromes were returned to normal and heme synthesis was restored. In mitochondria carrying the mutant Isu1 and no frataxin, Fe-S cluster enzyme activities were improved. The efficiency of new Fe-S cluster synthesis in isolated mitochondria was markedly increased compared with frataxin-minus cells, although the response to added iron was minimal. The M107I substitution in the highly conserved Isu scaffold protein is typically found in bacterial orthologs, suggesting that a unique feature of the bacterial Fe-S cluster machinery may be involved. The mechanism by which the mutant Isu bypasses the absence of frataxin remains to be determined but could be related to direct effects on Fe-S cluster assembly and/or indirect effects on mitochondrial iron availability.

Date: Sep. 21, 2011

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