Cellular and Mitochondrial Remodeling upon Defects in Iron-Sulfur Protein Biogenesis

Hausmann, Anja; Samans, Birgit; Lill, Roland; Mühlenhoff, Ulrich

doi:10.1074/jbc.m705570200

Cited by 105 publications

(162 citation statements)

References 70 publications

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“…3C). Second, Fdx2 was able to complement the defect in heme synthesis (29,30), as indicated by measuring the activity of the heme-dependent catalase. Third, the severe defect in COX activity in Yah1-depleted Gal-YAH1 cells (15) was fully rescued by synthesis of Fdx2, indicating that human Fdx2 can participate not only in yeast mitochondrial Fe/S cluster synthesis but also replace Yah1 function in the hydroxylation of heme O to heme A.…”

Section: Resultsmentioning

confidence: 99%

“…To analyze if Fdx2 can replace all functions of Yah1, we analyzed several biochemical parameters associated with functional loss of Yah1, including defective Fe/S protein biogenesis, heme biosynthesis, and iron regulation (29,30). First, expression of Fdx2 restored the activity of the Fe/S protein aconitase to the same levels as yeast Yah1 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Unlike in humans, Saccharomyces cerevisiae FC does not contain an Fe/S cluster, though blockage in Fe/S protein biogenesis in both species results in decreased heme production (30,40). Given the intimate connection between the two major iron-utilizing pathways, heme and Fe/S cluster biosynthesis, it is not surprising that cellular iron metabolism is directly regulated by the cell's capacity to generate Fe/S clusters (40).…”

Section: Discussionmentioning

confidence: 99%

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

Sheftel

Stehling

Pierik

et al. 2010

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

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Mammalian adrenodoxin (ferredoxin 1; Fdx1) is essential for the synthesis of various steroid hormones in adrenal glands. As a member of the [2Fe-2S] cluster-containing ferredoxin family, Fdx1 reduces mitochondrial cytochrome P450 enzymes, which then catalyze; e.g., the conversion of cholesterol to pregnenolone, aldosterone, and cortisol. The high protein sequence similarity between Fdx1 and its yeast adrenodoxin homologue (Yah1) suggested that Fdx1, like Yah1, may be involved in the biosynthesis of heme A and Fe/S clusters, two versatile and essential protein cofactors. Our study, employing RNAi technology to deplete human Fdx1, did not confirm this expectation. Instead, we identified a Fdx1-related mitochondrial protein, designated ferredoxin 2 (Fdx2) and found it to be essential for heme A and Fe/S protein biosynthesis. Unlike Fdx1, Fdx2 was unable to efficiently reduce mitochondrial cytochromes P450 and convert steroids, indicating that the two ferredoxin isoforms are highly specific for their substrates in distinct biochemical pathways. Moreover, Fdx2 deficiency had a severe impact, via impaired Fe/S protein biogenesis, on cellular iron homeostasis, leading to increased cellular iron uptake and iron accumulation in mitochondria. We conclude that mammals depend on two distinct mitochondrial ferredoxins for the specific production of either steroid hormones or heme A and Fe/S proteins.adrenodoxin | cytochrome P450 | iron | iron-sulfur cluster | IRP1

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Sheftel

Stehling

Pierik

et al. 2010

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

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“…In fact, intracellular iron is used in the build-up of Fe-S clusters, which are necessary for the regulation of mitochondrial oxidative processes [17].…”

Section: Introductionmentioning

confidence: 99%

Fine-tuned iron availability is essential to achieve optimal adipocyte differentiation and mitochondrial biogenesis

et al. 2014

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Aims/hypothesis Adipose tissue from obese and insulinresistant individuals showed altered expression of several iron-related genes in a recent study, suggesting that iron might have an important role in adipogenesis. To investigate this possible role, we aimed to characterise the effects of iron on adipocyte differentiation. Methods Intracellular iron deficiency was achieved using two independent approaches: deferoxamine administration (20 and 100 μmol/l) and transferrin knockdown (TF KD). The effects of added FeSO 4 , holo-transferrin and palmitate were studied during human and 3T3-L1 adipocyte differentiation. Finally, the relationship between iron-related and mitochondrialrelated genes was investigated in human adipose tissue. Results Most adipose tissue iron-related genes were predominantly expressed in adipocytes compared with stromal vascular cells. Of note, transferrin gene and protein expression increased significantly during adipocyte differentiation. Both deferoxamine and TF KD severely blunted adipocyte differentiation in parallel with increased inflammatory mRNAs. These effects were reversed in a dose-dependent manner after iron supplementation. Palmitate administration also led to a state of functional intracellular iron deficiency, with decreased Tf gene expression and iron uptake during adipocyte differentiation, which was reversed with transferrin co-treatment. On the other hand, iron in excess impaired differentiation, but this antiadipogenic effect was less pronounced than under iron chelation. Of interest, expression of several genes involved in mitochondrial biogenesis occurred in parallel with expression of iron-related genes both during adipogenesis and in human adipose tissue. Conclusions/interpretation Precise and fine-tuned iron availability is essential to achieve optimal adipocyte differentiation, possibly modulating adipocyte mitochondrial biogenesis.

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“…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. These observations are consistent with the localization of the FeS cluster biogenesis machinery and key FeS protein metabolic functions in mitochondria (16,23).…”

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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.

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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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Cellular and Mitochondrial Remodeling upon Defects in Iron-Sulfur Protein Biogenesis

Cited by 105 publications

References 70 publications

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

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

Fine-tuned iron availability is essential to achieve optimal adipocyte differentiation and mitochondrial biogenesis

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

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