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Abstract
Iron is an essential element for life. At some level, iron is involved in almost every biological pathway. A breakdown in iron regulation results in a variety of human disorders and diseases. Iron deficiency is the most common and widespread nutritional disorder worldwide. On the other hand, iron overload is implicated in diseases such as hemochromatosis, Parkinson's, Alzeheimer's, and the cardio- and neuro-degenerative disease Freidreich's Ataxia (FRDA). Events that take place within the mitochondria strongly dictate overall cellular iron regulation. Therefore, the main goal of this research is to understand the fundamental events of mitochondrial iron regulation. This has a direct impact on our knowledge, and eventual treatment of these disorders.
FRDA results from low expression levels of a single protein, 'frataxin.' Frataxin, which is nuclear encoded but targeted to the matrix of the mitochondria, has been implicated in numerous aspects of mitochondrial iron homeostasis. Specifically, frataxin has been shown to be an iron chaperone for the highly conserved and essential Iron Sulfur Cluster (ISC) bioassembly pathway. An understanding of the molecular details of the ISC pathway is critical if we hope to fight against FRDA and other metal disregrulation disorders.
Research presented here shows monomeric frataxin is able to bind ferrous iron via carboxylate ligands and maintain metal bioavailability under physiologically relevant conditions. The protein is able to provide iron to the ISC pathway via a metal dependent protein:protein interaction with the scaffold protein (called ISU) on which the clusters are built. ISU proteins initially bind iron at a distinct acceptance site separate from the well-documented 3-Cys active site. Specific acidic residues of frataxin's Site II iron binding site are essential for iron delivery to the scaffold for both in vitro and in vivo iron-sulfur cluster assembly. This report directly addresses questions regarding mitochondrial iron homeostasis by providing previously unknown atomic details of the initial steps during Fe-S cluster bioassembly.
