O’Neill, Heather A.

Numerous degenerative disorders are associated with elevated levels of prooxidants and declines in mitochondrial aconitase activity. Deficiency in the mitochondrial iron-binding protein frataxin results in diminished activity of various mitochondrial iron-sulfur 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.