Iron–sulfur cluster biogenesis and human disease

Abstract

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...

Humans possess two mitochondrial ferredoxins, Fdx1 and Fdx2, with distinct roles in steroidogenesis, heme, and Fe/S cluster biosynthesis

“…2). When cellular Fe/S cluster assembly becomes limiting (e.g., due to low iron availability or upon defects of the biogenesis machineries), IRP1 loses its Fe/S cluster thereby gaining the ability to bind to stem-loop structures of mRNAs encoding several proteins involved in iron homeostasis (9,34). IRP1 functions together with the related IRP2 that does not bind an Fe/S cluster, yet is degraded under iron-replete conditions.…”

“…20). It is generally assumed from the high sequence similarity of mammalian adrenodoxin and yeast Yah1 that the former protein is also capable of catalyzing the biosynthesis of Fe/S clusters and heme A (9,10,13,15). In the current study, we tested this assumption for human adrenodoxin (Fdx1).…”

An Allelic Mutant Series of ATM3 Reveals Its Key Role in the Biogenesis of Cytosolic Iron-Sulfur Proteins in Arabidopsis

“…In yeast and human, dysfunction of Atm1p and ABCB7, respectively, leads to constitutive expression of iron-uptake genes and accumulation of iron in the mitochondria (Lill and Mü hlenhoff, 2008;Rouault and Tong, 2008). To investigate whether this is the case in Figure 4.…”

“…Mutations in the human ortholog ABCB7 are the cause of X-linked sideroblastic anemia with ataxia, in which one of the symptoms is mitochondrial iron overload (Rouault and Tong, 2008). Moreover, ATMs are widespread and highly conserved in b-proteobacteria and could be involved in nickel and cobalt resistance (Mikolay and Nies, 2009).…”

Analysis of iron–sulfur protein maturation in eukaryotes

“…The crucial importance of Fe/S proteins and their assembly machineries has been recognized by virtue of the association of lesions in ISC machinery genes with three human diseases (for a review, see refs. 3,24). First, a GAA triplet repeat expansion in an intronic region of frataxin is the most frequent cause of Friedreich ataxia, an autosomal recessive neurodegenerative disorder 25 .…”