Iron-sulfur (Fe-S) clusters are essential for numerous biological processes, including mitochondrial respiratory chain activity and various other enzymatic and regulatory functions. Human Fe-S cluster assembly proteins are frequently encoded by single genes, and inherited defects in some of these genes cause disease. Recently, the spectrum of diseases attributable to abnormal Fe-S cluster biogenesis has extended beyond Friedreich ataxia to include a sideroblastic anemia with deficiency of glutaredoxin 5 and a myopathy associated with a deficiency of a Fe-S cluster assembly scaffold protein, ISCU. Mutations within other mammalian Fe-S cluster assembly genes could be causative for human diseases that manifest distinctive combinations of tissue-specific impairments. Thus, defects in the iron-sulfur cluster biogenesis pathway could underlie many human diseases.
Iron-sulfur proteins: biological roles and relevanceIron-sulfur (Fe-S) clusters are ancient biological prosthetic groups that are essential for many fundamental processes including photosynthesis and respiration (reviewed in Refs. [1,2]). The most common Fe-S clusters in eukaryotes are the [2Fe-2S] and [4Fe-4S] clusters, which are formed by tetrahedrally coordinated iron atoms with bridging sulfides and are most often ligated to the protein through cysteine residues. The chemical reactivities of iron and sulfur, together with variations in the composition, redox potential, oxidation state, physical accessibility of the cluster and effects of the local protein environment, enable these versatile cofactors to accept or donate single electrons, catalyze enzymatic reactions or function as regulatory proteins. For instance, Fe-S clusters are essential components of respiratory electron transfer complexes as well as the tricarboxylic acid cycle (TCA cycle) enzymes, aconitase and succinate dehydrogenase ( Figure 1a). In addition, the Fe-S clusters within DNA repair enzymes Fanconi anemia group J protein (FancJ) and Xeroderma pigmentosum group D protein (XPD) facilitate DNA damage recognition and repair [3]. Moreover, Fe-S cluster assembly and disassembly in mammalian iron regulatory protein-1 (IRP1) alters the active site conformation and accessibility and determines whether IRP1 binds its mRNA targets in response to oxidative stress and intracellular iron levels (reviewed in Refs. [4][5][6]).Because Fe-S clusters play a critical role in a wide range of cellular activities, significant disruptions in Fe-S cluster biogenesis and repair are expected to also affect numerous basic cellular processes (Figure 1b). Indeed, defects in this important biological pathway are now recognized as the cause of several human diseases. Over the last decade, studies of Friedriech ataxia revealed that deficiency of the protein frataxin (FXN) results in the loss of Fe-S protein activities, mitochondrial iron overload, oxidative damage and ultimately mitochondrial failure [7]. In the last 2 years, defects in Fe-S cluster assembly genes have been shown to be responsible for two m...