Numerous degenerative disorders are associated with elevated levels of pro-oxidants and declines in mitochondriat aconitase activity. Deficiency in the mitochondrial iron-binding protein frataxin results in diminished activity of various mitochondriat iron-sutfur proteins including aconitase. We found that aconitase can undergo reversible citrate-dependent modulation in activity in response to pro-oxidants. Frataxin interacted with aconitase in a citrate-dependent fashion, reduced the level of oxidant-induced inactivation, and converted inactive [3Fe-4S]1+ enzyme to the active [4Fe-4S] 2+ form of the protein. Thus, frataxin is an iron chaperone protein that protects the aconitase [4Fe-4S]2+ cluster from disassembly and promotes enzyme reactivation.
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