Regulation of Mitochondrial Iron Accumulation by Yfh1p, a Putative Homolog of Frataxin

Babcock, Michael; Silva, Deepika de; Oaks, Robert D.; Davis‐Kaplan, Sandra; Jiralerspong, Sarn; Montermini, Laura; Pandolfo, Massimo; Kaplan, Jerry

doi:10.1126/science.276.5319.1709

Cited by 876 publications

(744 citation statements)

References 23 publications

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“…This suggests that Aft1p is involved in the intracellular decomplexation of siderophores. Another observation supports the hypothesis that ferric siderophores are normally not accumulated inside the cells : in cells deleted for the YFH1 gene, reductive iron uptake is constitutively increased, iron accumulates into the mitochondria and is toxic (Babcock et al, 1997). The non-reductive uptake of FOB or FCH (but interestingly not of TAF) is also constitutively increased in ∆yfh1 mutants (data not shown).…”

Section: Intracellular Fate Of Ironsupporting

confidence: 70%

“…Analysis of new mutants also indicated that each Sitp member is not completely specific for a single siderophore. Cells lacking the YFH1 gene are sensitive to iron (Babcock et al, 1997), especially when it is presented as FOB, FC or FCH (see below). We used this property to select new mutants able to grow on plates enriched with 10 µM FCH.…”

Section: The Specificity Of Sit1 and Homologues For Various Siderophomentioning

confidence: 99%

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Siderophore uptake and use by the yeast Saccharomyces cerevisiae

et al. 2001

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The non-reductive uptake of several siderophores (ferrioxamine B, ferrichrome, triacetylfusarinine C and ferricrocin) by various strains of Saccharomyces cerevisiae was studied. Several aspects of siderophore transport were examined, including specificity of transport, regulation of transport and intracellular localization of the ferri-siderophores. Ferrioxamine B was taken up preferentially via the products of the SIT1 gene and triacetylfusarinine C by the TAF1 gene product, but the specificity was not absolute. Ferrichrome and ferricrocin uptake was not dependent on a single major facilitator superfamily (MFS) gene product. The apparent specificity of transport was strongly dependent on the genetic background of the cells. Non-reductive uptake of siderophores was induced under more stringent conditions (of iron deprivation) than was the reductive uptake of ferric citrate. Regulation of transport depended on the transcriptional factors Aft1 and Tup1/Ssn6. Cells disrupted for the TUP1 or SSN6 genes were constitutively derepressed for the uptake of ferrichrome, ferricrocin or ferrioxamine B, but not for the uptake of triacetylfusarinine C. Cells bearing the AFT1 up mutation accumulated large amounts of ferric siderophores. Intracellular decomplexation of the siderophores occurred when transcription of the AFT1 up gene was repressed. Ferrioxamine B and ferrichrome seemed to accumulate in an endosomal compartment, as shown by biochemical studies and by confocal microscopy study of cells loaded with a fluorescent derivative of ferrichrome. Endocytosis was, however, not involved in the non-reductive uptake of siderophores.

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Section: Intracellular Fate Of Ironsupporting

confidence: 70%

Section: The Specificity Of Sit1 and Homologues For Various Siderophomentioning

confidence: 99%

Siderophore uptake and use by the yeast Saccharomyces cerevisiae

et al. 2001

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“…On the other hand, iron deposits have been demonstrated in the heart of FRDA patients. Although the actual function of frataxin is not yet clear, these findings suggest that FRDA patients suffer from free radical toxicity causing mitochondrial dysfunction 6 .…”

mentioning

confidence: 80%

Clinical and molecular studies in five Brazilian cases of Friedreich ataxia

Schwartz

Jardim

Puga

et al. 1999

Arq. Neuro-Psiquiatr.

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-Friedreich ataxia (FRDA), the most common autosomal recessive ataxia, is caused in 94% of cases by homozygous expansions of an unstable GAA repeat localised in intron 1 of the X25 gene. We have investigated this mutation in five Brazilian patients: four with typical FRDA findings and one patient with atypical manifestations, who was considered to have some other form of cerebellar ataxia with retained reflexes. The GAA expansion was detected in all these patients. The confirmation of FRDA diagnosis in the atypical case may be pointing out, as in other reports, that clinical spectrum of Friedreich's ataxia is broader than previously recognised and includes cases with intact tendon reflexes.KEY WORDS: Friedreich ataxia, cerebellar ataxia, expansion of unstable repeats. Avaliação clínica e molecular de cinco pacientes brasileiros com ataxia de FriedreichRESUMO -A ataxia de Friedreich (FRDA) é a mais frequente das ataxias com herança autossômica recessiva. Em 94 % dos casos, é causada por uma expansão homozigota instável da repetição de trinucleotídeos GAA, localizada no primeiro íntron do gene X25. Esta mutação foi investigada em cinco pacientes brasileiros: quatro com quadro clínico típico de FRDA e um paciente com manifestações atípicas, cujo diagnóstico prévio era o de alguma outra forma de ataxia cerebelar com preservação de reflexos. A investigação foi positiva nos cinco casos. A confirmação do diagnóstico de FRDA

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“…1,2 Knockout of the FXN homolog Yfh1p in yeasts impairs respiration and causes mitochondrial DNA depletion and iron accumulation. 3,4 Defects of iron-sulfur proteins in myocardial biopsies of FRDA patients confirmed a defective iron-sulfur cluster (ISC) biogenesis in the Yfh1p knockout model. 5 According to the current view, mammalian FXN is directly involved in ISC biogenesis, 6 the central steps of which take place in the mitochondrial matrix.…”

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confidence: 99%

Dual role of the mitochondrial protein frataxin in astrocytic tumors

Kirches

Andrae

Hoefer

et al. 2011

Laboratory Investigation

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The mitochondrial protein frataxin (FXN) is known to be involved in mitochondrial iron homeostasis and iron-sulfur cluster biogenesis. It is discussed to modulate function of the electron transport chain and production of reactive oxygen species (ROS). FXN loss in neurons and heart muscle cells causes an autosomal-dominant mitochondrial disorder, Friedreich's ataxia. Recently, tumor induction after targeted FXN deletion in liver and reversal of the tumorigenic phenotype of colonic carcinoma cells following FXN overexpression were described in the literature, suggesting a tumor suppressor function. We hypothesized that a partial reversal of the malignant phenotype of glioma cells should occur after FXN transfection, if the mitochondrial protein has tumor suppressor functions in these brain tumors. In astrocytic brain tumors and tumor cell lines, we observed reduced FXN levels compared with non-neoplastic astrocytes. Mitochondrial content (citrate synthase activity) was not significantly altered in U87MG glioblastoma cells stably overexpressing FXN (U87-FXN). Surprisingly, U87-FXN cells exhibited increased cytoplasmic ROS levels, although mitochondrial ROS release was attenuated by FXN, as expected. Higher cytoplasmic ROS levels corresponded to reduced activities of glutathione peroxidase and catalase, and lower glutathione content. The defect of antioxidative capacity resulted in increased susceptibility of U87-FXN cells against oxidative stress induced by H 2 O 2 or buthionine sulfoximine. These characteristics may explain a higher sensitivity toward staurosporine and alkylating drugs, at least in part. On the other hand, U87-FXN cells exhibited enhanced growth rates in vitro under growth factor-restricted and hypoxic conditions and in vivo using tumor xenografts in nude mice. These data contrast to a general tumor suppressor function of FXN but suggest a dual, pro-proliferative but chemosensitizing role in astrocytic tumors.

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Regulation of Mitochondrial Iron Accumulation by Yfh1p, a Putative Homolog of Frataxin

Cited by 876 publications

References 23 publications

Siderophore uptake and use by the yeast Saccharomyces cerevisiae

Siderophore uptake and use by the yeast Saccharomyces cerevisiae

Clinical and molecular studies in five Brazilian cases of Friedreich ataxia

Dual role of the mitochondrial protein frataxin in astrocytic tumors

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