The Yeast Scaffold Proteins Isu1p and Isu2p Are Required inside Mitochondria for Maturation of Cytosolic Fe/S Proteins

Gerber, Jana; Neumann, K.; Prohl, Corinna; Mühlenhoff, Ulrich; Lill, Roland

doi:10.1128/mcb.24.11.4848-4857.2004

Cited by 108 publications

(106 citation statements)

References 72 publications

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“…28) has raised the issue of whether they might function in Fe͞S protein maturation in these compartments. Two recent studies render this possibility unlikely (29,30). First, both the cysteine desulfurase Nfs1p and the scaffold proteins Isu1p and Isu2p have been shown to be necessary inside mitochondria for successful participation in Fe͞S protein maturation in the cytosol.…”

Section: Discussionmentioning

confidence: 99%

The eukaryotic P loop NTPase Nbp35: An essential component of the cytosolic and nuclear iron–sulfur protein assembly machinery

Hausmann

Netz²,

Balk³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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152

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Section: Discussionmentioning

confidence: 99%

The eukaryotic P loop NTPase Nbp35: An essential component of the cytosolic and nuclear iron–sulfur protein assembly machinery

Hausmann

Netz²,

Balk³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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152

161

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“…5B), consistent with permanent mitochondrial DNA damage (rho mutations). Rapid loss of mitochondrial DNA is typically seen in yeast cells defective in iron-sulfur biogenesis (17,23,36,(41)(42)(43). Despite this dominant negative effect of D71A Isu1p on WT mitochondria, there was no loss in Sod2p activity (Fig.…”

Section: ) That Was Rescued By Iron Chelation (Lane 3)mentioning

confidence: 99%

“…Another component of the iron-sulfur biogenesis pathway is the yeast Isu proteins (also known as IscU in bacteria and ISCU in mammals) onto which labile iron-sulfur scaffolds are built (17)(18)(19)(20)(21)(22)35). A combined deletion in S. cerevisiae ISU1 and ISU2 is lethal (18, 35); hence we expressed ISU1 under the repressible S. cerevisiae GAL1 promoter in a isu1⌬ isu2⌬ background.…”

Section: ) That Was Rescued By Iron Chelation (Lane 3)mentioning

confidence: 99%

“…One of the key components is a well conserved iron-sulfur scaffold protein originally described for bacteria as IscU, also known as mammalian ISCU and S. cerevisiae Isu1p and Isu2p, referred collectively herein as "Isu proteins" (17)(18)(19)(20)(21)(22). The iron-sulfur clusters on Isu proteins are labile and can be transferred to target iron-sulfur proteins through the aid of mitochondrial factors including Grx5p and Ssq1p (15,16).…”

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confidence: 99%

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The Interaction of Mitochondrial Iron with Manganese Superoxide Dismutase

Naranuntarat

Jensen

Pazicni

et al. 2009

Journal of Biological Chemistry

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Superoxide dismutase 2 (SOD2) is one of the rare mitochondrial enzymes evolved to use manganese as a cofactor over the more abundant element iron. Although mitochondrial iron does not normally bind SOD2, iron will misincorporate into Saccharomyces cerevisiae Sod2p when cells are starved for manganese or when mitochondrial iron homeostasis is disrupted by mutations in yeast grx5, ssq1, and mtm1. We report here that such changes in mitochondrial manganese and iron similarly affect cofactor selection in a heterologously expressed Escherichia coli Mn-SOD, but not a highly homologous Fe-SOD. By x-ray absorption near edge structure and extended x-ray absorption fine structure analyses of isolated mitochondria, we find that misincorporation of iron into yeast Sod2p does not correlate with significant changes in the average oxidation state or coordination chemistry of bulk mitochondrial iron. Instead, small changes in mitochondrial iron are likely to promote iron-SOD2 interactions. Iron binds Sod2p in yeast mutants blocking late stages of iron-sulfur cluster biogenesis (grx5, ssq1, and atm1), but not in mutants defective in the upstream Isu proteins that serve as scaffolds for iron-sulfur biosynthesis. In fact, we observed a requirement for the Isu proteins in iron inactivation of yeast Sod2p. Sod2p activity was restored in mtm1 and grx5 mutants by depleting cells of Isu proteins or using a dominant negative Isu1p predicted to stabilize iron binding to Isu1p. In all cases where disruptions in iron homeostasis inactivated Sod2p, we observed an increase in mitochondrial Isu proteins. These studies indicate that the Isu proteins and the iron-sulfur pathway can donate iron to Sod2p.Metal-containing enzymes are generally quite specific for their cognate cofactor. Misincorporation of the wrong metal ion can be deleterious and tends to be a rare occurrence in biology. A prime example of metal ion selectivity is illustrated by the family of manganese-and iron-containing superoxide dismutases (SODs) 3 . This large family of enzymes utilizes either manganese or iron as cofactors to scavenge superoxide anion.

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“…The cytosolic Fe-S assembly (CIA) pathway is involved in the maturation of [2Fe-2S] clusters into clusters and is capable of providing [4Fe-4S] clusters to cytosolic and nuclear proteins. Because of the absence of a cytosolic Cys desulfurase, the CIA pathway depends on the integrity of the mitochondrial Fe-S cluster machinery and a functional ABC transporter of the mitochondria (Kispal et al, 1999;Gerber et al, 2004). The three pathways share a common mechanism in which the Fe-S is preassembled on a scaffold protein and then transferred to apoproteins by carriers or targeting factors ( Fig.…”

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confidence: 99%

Glutaredoxin GRXS17 Associates with the Cytosolic Iron-Sulfur Cluster Assembly Pathway

et al. 2016

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Cytosolic monothiol glutaredoxins (GRXs) are required in iron-sulfur (Fe-S) cluster delivery and iron sensing in yeast and mammals. In plants, it is unclear whether they have similar functions. Arabidopsis (Arabidopsis thaliana) has a sole class II cytosolic monothiol GRX encoded by GRXS17. Here, we used tandem affinity purification to establish that Arabidopsis GRXS17 associates with most known cytosolic Fe-S assembly (CIA) components. Similar to mutant plants with defective CIA components, grxs17 loss-of-function mutants showed some degree of hypersensitivity to DNA damage and elevated expression of DNA damage marker genes. We also found that several putative Fe-S client proteins directly bind to GRXS17, such as XANTHINE DEHYDROGENASE1 (XDH1), involved in the purine salvage pathway, and CYTOSOLIC THIOURIDYLASE SUBUNIT1 and CYTOSOLIC THIOURIDYLASE SUBUNIT2, both essential for the 2-thiolation step of 5-methoxycarbonylmethyl-2-thiouridine (mcm 5 s 2 U) modification of tRNAs. Correspondingly, profiling of the grxs17-1 mutant pointed to a perturbed flux through the purine degradation pathway and revealed that it phenocopied mutants in the elongator subunit ELO3, essential for the mcm 5 tRNA modification step, although we did not find XDH1 activity or tRNA thiolation to be markedly reduced in the grxs17-1 mutant. Taken together, our data suggest that plant cytosolic monothiol GRXs associate with the CIA complex, as in other eukaryotes, and contribute to, but are not essential for, the correct functioning of client Fe-S proteins in unchallenged conditions.

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The Yeast Scaffold Proteins Isu1p and Isu2p Are Required inside Mitochondria for Maturation of Cytosolic Fe/S Proteins

Cited by 108 publications

References 72 publications

The eukaryotic P loop NTPase Nbp35: An essential component of the cytosolic and nuclear iron–sulfur protein assembly machinery

The eukaryotic P loop NTPase Nbp35: An essential component of the cytosolic and nuclear iron–sulfur protein assembly machinery

The Interaction of Mitochondrial Iron with Manganese Superoxide Dismutase

Glutaredoxin GRXS17 Associates with the Cytosolic Iron-Sulfur Cluster Assembly Pathway

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