Bacterial frataxin CyaY is the gatekeeper of iron-sulfur cluster formation catalyzed by IscS

Adinolfi, Salvatore; Iannuzzi, Clara; Prischi, Filippo; Pastore, Chiara; Iametti, Stefania; Martin, Stephen R.; Bonomi, Francesco; Pastore, Annalisa

doi:10.1038/nsmb.1579

Cited by 229 publications

(327 citation statements)

References 36 publications

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“…Lack of frataxin would lead to the formation of highly reactive iron forms that inactivate iron-sulfur-containing enzymes. The second one suggests that, rather than acting as the iron donor for ironsulfur biogenesis, frataxin senses mitochondrial iron content and regulates the rate of iron-sulfur biogenesis (53). This second hypothesis would explain the interactions observed between frataxin and members of the iron-sulfur biosynthetic machinery (11)(12)(13), as well as its iron binding properties (54).…”

Section: Discussionmentioning

confidence: 99%

Frataxin Depletion in Yeast Triggers Up-regulation of Iron Transport Systems before Affecting Iron-Sulfur Enzyme Activities

Moreno-Cermeño

Òbis

Bellı́

et al. 2010

Journal of Biological Chemistry

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The primary function of frataxin, a mitochondrial protein involved in iron homeostasis, remains controversial. Using a yeast model of conditional expression of the frataxin homologue YFH1, we analyzed the primary effects of YFH1 depletion. The main conclusion unambiguously points to the upregulation of iron transport systems as a primary effect of YFH1 down-regulation. We observed that inactivation of aconitase, an iron-sulfur enzyme, occurs long after the iron uptake system has been activated. Decreased aconitase activity should be considered part of a group of secondary events promoted by iron overloading, which includes decreased superoxide dismutase activity and increased protein carbonyl formation. Impaired manganese uptake, which contributes to superoxide dismutase deficiency, has also been observed in YFH1-deficient cells. This low manganese content can be attributed to the down-regulation of the metal ion transporter Smf2. Low Smf2 levels were not observed in AFT1/YFH1 double mutants, indicating that high iron levels could be responsible for the Smf2 decline. In summary, the results presented here indicate that decreased iron-sulfur enzyme activities in YFH1-deficient cells are the consequence of the oxidative stress conditions suffered by these cells.

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Section: Discussionmentioning

confidence: 99%

Frataxin Depletion in Yeast Triggers Up-regulation of Iron Transport Systems before Affecting Iron-Sulfur Enzyme Activities

Moreno-Cermeño

Òbis

Bellı́

et al. 2010

Journal of Biological Chemistry

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“…Intriguingly, and in stark contrast to the mammalian system, this effect of Yfh1 was independent of the presence of ISCU. In bacteria, CyaY, the homologue of eukaryotic FXN, was shown to slow down rather than stimulate Fe-S assembly on the IscS-IscU complex 33 and did not alter the [2Fe2S]:[4Fe4S] cluster ratio 34 . These contrasting data raise important questions concerning the molecular function of FXN, (both in bacteria and mammals), and the mechanism by which FXN stimulates sulfide production and the rates of Fe-S cluster assembly.…”

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confidence: 99%

Mammalian frataxin directly enhances sulfur transfer of NFS1 persulfide to both ISCU and free thiols

et al. 2015

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Friedreich's ataxia is a severe neurodegenerative disease caused by the decreased expression of frataxin, a mitochondrial protein that stimulates iron-sulfur (Fe-S) cluster biogenesis. In mammals, the primary steps of Fe-S cluster assembly are performed by the NFS1-ISD11-ISCU complex via the formation of a persulfide intermediate on NFS1. Here we show that frataxin modulates the reactivity of NFS1 persulfide with thiols. We use maleimide-peptide compounds along with mass spectrometry to probe cysteine-persulfide in NFS1 and ISCU. Our data reveal that in the presence of ISCU, frataxin enhances the rate of two similar reactions on NFS1 persulfide: sulfur transfer to ISCU leading to the accumulation of a persulfide on the cysteine C104 of ISCU, and sulfur transfer to small thiols such as DTT, L-cysteine and GSH leading to persulfuration of these thiols and ultimately sulfide release. These data raise important questions on the physiological mechanism of Fe-S cluster assembly and point to a unique function of frataxin as an enhancer of sulfur transfer within the NFS1-ISD11-ISCU complex.

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“…They appear in various compositions and confer upon FeS proteins the ability to accept or donate single electrons and/or iron, catalyze enzymatic reactions, or even function as regulatory proteins (17,18). Disruption of FeS cluster biogenesis is deleterious to vital cell processes in humans, leading to diseases such as Friedreich's ataxia (18,19), X-linked sideroblastic anemia with ataxia (XLSA/A) (20), and a form of sideroblastic anemia associated with a deletion in the GLRX5 gene (21). The accumulation of iron in mitochondria, which leads to misdistribution of the metal (22) and mismanagement of cellular iron regulatory properties (23,24), is a hallmark of various diseases.…”

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confidence: 99%

Facile transfer of [2Fe-2S] clusters from the diabetes drug target mitoNEET to an apo-acceptor protein

Zuris

Harir

Conlan

et al. 2011

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

120

176

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MitoNEET (mNT) is an outer mitochondrial membrane target of the thiazolidinedione diabetes drugs with a unique fold and a labile [2Fe-2S] cluster. The rare 1-His and 3-Cys coordination of mNT's [2Fe-2S] leads to cluster lability that is strongly dependent on the presence of the single histidine ligand (His87). These properties of mNT are similar to known [2Fe-2S] shuttle proteins. Here we investigated whether mNT is capable of cluster transfer to acceptor protein(s). cluster transfer is observed between oxidized mNT and apo-ferredoxin (a-Fd) using UV-VIS spectroscopy and native-PAGE, as well as with a mitochondrial iron detection assay in cells. The transfer is unidirectional, proceeds to completion, and occurs with a second-order-reaction rate that is comparable to known iron-sulfur transfer proteins. Mutagenesis of His87 with Cys (H87C) inhibits transfer of the [2Fe-2S] clusters to a-Fd. This inhibition is beyond that expected from increased cluster kinetic stability, as the equivalently stable Lys55 to Glu (K55E) mutation did not inhibit transfer. The H87C mutant also failed to transfer its iron to mitochondria in HEK293 cells. The diabetes drug pioglitazone inhibits iron transfer from WT mNT to mitochondria, indicating that pioglitazone affects a specific property, [2Fe-2S] cluster transfer, in the cellular environment. This finding is interesting in light of the role of iron overload in diabetes. Our findings suggest a likely role for mNT in [2Fe-2S] and/or iron transfer to acceptor proteins and support the idea that pioglitazone's antidiabetic mode of action may, in part, be to inhibit transfer of mNT's [2Fe-2S] cluster.CISD1 | diabetes | FeS cluster | oxidative stress M itoNEET (mNT) is a newly discovered target (1) of the insulin-sensitizing thiazolidinedione (TZD) class of type II diabetes drugs (2, 3), which interact with the canonical target PPARγ (4, 5). The interaction of TZD drugs with mNT has been proposed to be of therapeutic importance (1,6). This is the first iron-sulfur protein to be directly targeted by drug binding (1, 6). The protein contains two [2Fe-2S] clusters, which have been shown to be chemically labile (7). Initial characterization of mNT's redox active and pH labile [2Fe-2S] clusters show that both properties are modulated by binding of TZDs (6,8), indicating a direct interaction of the protein with the TZD drugs. A second related member of the human NEET protein family, Miner1, is structurally homologous to mNT (9). Miner1 has recently been linked to autophagy, apoptosis, and aging (10, 11), and mis-splicing is associated with a rare disease, known as Wolfram Syndrome 2 (12). Together, mNT and Miner1 represent a new class of NEET iron-sulfur (FeS) proteins characterized structurally by their unique homodimeric fold and rare 3-Cys-1-His [2Fe-2S] cluster ligand environment (6,9,13,14).Iron-sulfur (FeS) cluster-containing proteins are key players in many essential processes, such as photosynthesis, respiration, and nitrogen fixation (15, 16). They appear in various compositions and ...

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Bacterial frataxin CyaY is the gatekeeper of iron-sulfur cluster formation catalyzed by IscS

Cited by 229 publications

References 36 publications

Frataxin Depletion in Yeast Triggers Up-regulation of Iron Transport Systems before Affecting Iron-Sulfur Enzyme Activities

Frataxin Depletion in Yeast Triggers Up-regulation of Iron Transport Systems before Affecting Iron-Sulfur Enzyme Activities

Mammalian frataxin directly enhances sulfur transfer of NFS1 persulfide to both ISCU and free thiols

Facile transfer of [2Fe-2S] clusters from the diabetes drug target mitoNEET to an apo-acceptor protein

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