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Gene Review

YFH1  -  Yfh1p

Saccharomyces cerevisiae S288c

Synonyms: Frataxin homolog, mitochondrial, YDL120W
 
 
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Disease relevance of YFH1

  • Characterizing the mechanism by which YFH1 regulates iron homeostasis in yeast may help to define the pathologic process leading to cell damage in Friedreich's ataxia [1].
  • Whereas the function of fxn is unknown, the yeast frataxin homolog (Yfh1p) has been shown to be involved in mitochondrial iron homeostasis and protection from free radical toxicity [2].
  • We have compared the properties of three proteins from the frataxin family--the bacterial CyaY from Escherichia coli, the yeast Yfh1 and human frataxin--as representative of organisms of increasing complexity [3].
 

High impact information on YFH1

  • The YFH1-homologous domain of frataxin functions in yeast and a disease-associated missense mutation of this domain, or the corresponding domain in YFH1, reduces function [4].
  • In the absence of Yfh1p, activity of Fe-S-containing enzymes (aconitase, succinate dehydrogenase) is decreased, whereas the activity of a non-Fe-S-containing enzyme (malate dehydrogenase) is unaffected [5].
  • When delta YFH1 cells were grown in raffinose medium, the formation of holo-ferredoxin was low, as a consequence of the decrease in ferredoxin precursor import into mitochondria [6].
  • A deficiency of this protein in humans causes Friedreich's ataxia, while its complete absence in yeast (Delta yfh1 mutant) results in loss of mitochondrial DNA, apparently due to radicals generated by excess iron [7].
  • Mutations blocking the first or the second cleavage of Yfh1p do not interfere with its in vitro import or with its ability to complement phenotypes of the Delta yfh1 mutant strain [8].
 

Biological context of YFH1

  • In spite of their apparent roles in cellular iron homeostasis, we find that the expression of neither ATM1 nor YFH1 is responsive to cellular iron status [9].
  • A similar strong decline was observed with extracts from Delta yfh1 mitochondria, indicating that both Isa1p and the yeast frataxin homologue, Yfh1p, are crucial for biogenesis of mitochondrial Fe/S proteins [10].
  • Further, overexpression of Yfh1p has no effect on oxygen consumption in wild-type yeast grown in either fermentative or respiratory carbon sources [11].
  • The yeast frataxin homologue (yfh1p) is required for cellular respiration [12].
 

Anatomical context of YFH1

  • Yeast strains with a deletion in the frataxin homologue YFH1 accumulate excess iron in mitochondria and demonstrate mitochondrial damage [13].
  • Reintroduction of YFH1 results in the rapid export of accumulated mitochondrial iron into the cytosol as free, non-heme bound iron, demonstrating that mitochondrial iron in the yeast FA model can be made bioavailable [13].
 

Associations of YFH1 with chemical compounds

  • The effect of ras2 mutation on the growth of yfh1 null strain was masked by the addition of caffeine [14].
  • These data suggest that the activity of Yfh1p is not essential in cells grown on glycerol [15].
  • It has been reported that alanine substitution of residues in an acidic ridge of yeast frataxin (Yfh1) elicits loss of iron binding in vitro but has no effect on Fe-S cluster synthesis in vivo [16].
  • Here, we show that Yfh1 specifically binds to the central Fe/S-cluster (ISC)-assembly complex, which is composed of the scaffold protein Isu1 and the cysteine desulphurase Nfs1 [17].
 

Other interactions of YFH1

  • We show here that MRS4 is co-regulated with the iron regulon genes, and up-regulated in a strain deficient for Yfh1p, the yeast homologue of human frataxin [18].
  • The double yfh1 ras2 mutant has increased mRNA levels of CIT2 gene and augmented catalase activity [14].
  • A synthetic lethal screen on high iron media with the mild G107D yfh1 mutant has specifically identified Isu1p [19].
  • In jac1 mutants, like in ssq1 mutants, processing of the Yfh1p precursor protein from intermediate to mature forms was delayed [20].
  • We investigated the role of Tim44 in the biogenesis of the authentic mitochondrial protein Yfh1p, the yeast homolog of mammalian frataxin, which was recently implicated in Friedreich ataxia [21].

References

  1. Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin. Babcock, M., de Silva, D., Oaks, R., Davis-Kaplan, S., Jiralerspong, S., Montermini, L., Pandolfo, M., Kaplan, J. Science (1997) [Pubmed]
  2. Human frataxin maintains mitochondrial iron homeostasis in Saccharomyces cerevisiae. Cavadini, P., Gellera, C., Patel, P.I., Isaya, G. Hum. Mol. Genet. (2000) [Pubmed]
  3. A structural approach to understanding the iron-binding properties of phylogenetically different frataxins. Adinolfi, S., Trifuoggi, M., Politou, A.S., Martin, S., Pastore, A. Hum. Mol. Genet. (2002) [Pubmed]
  4. Respiratory deficiency due to loss of mitochondrial DNA in yeast lacking the frataxin homologue. Wilson, R.B., Roof, D.M. Nat. Genet. (1997) [Pubmed]
  5. Inhibition of Fe-S cluster biosynthesis decreases mitochondrial iron export: evidence that Yfh1p affects Fe-S cluster synthesis. Chen, O.S., Hemenway, S., Kaplan, J. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  6. A non-essential function for yeast frataxin in iron-sulfur cluster assembly. Duby, G., Foury, F., Ramazzotti, A., Herrmann, J., Lutz, T. Hum. Mol. Genet. (2002) [Pubmed]
  7. The mitochondrial protein frataxin prevents nuclear damage. Karthikeyan, G., Lewis, L.K., Resnick, M.A. Hum. Mol. Genet. (2002) [Pubmed]
  8. Distinct roles for two N-terminal cleaved domains in mitochondrial import of the yeast frataxin homolog, Yfh1p. Gordon, D.M., Kogan, M., Knight, S.A., Dancis, A., Pain, D. Hum. Mol. Genet. (2001) [Pubmed]
  9. The role of the mitochondrion in cellular iron homeostasis. Schueck, N.D., Woontner, M., Koeller, D.M. Mitochondrion (2001) [Pubmed]
  10. Characterization of iron-sulfur protein assembly in isolated mitochondria. A requirement for ATP, NADH, and reduced iron. Mühlenhoff, U., Richhardt, N., Gerber, J., Lill, R. J. Biol. Chem. (2002) [Pubmed]
  11. YFH1-mediated iron homeostasis is independent of mitochondrial respiration. Chen, O.S., Kaplan, J. FEBS Lett. (2001) [Pubmed]
  12. Iron metabolism in mice with partial frataxin deficiency. Santos, M.M., Miranda, C.J., Levy, J.E., Montross, L.K., Cossée, M., Sequeiros, J., Andrews, N., Koenig, M., Pandolfo, M. Cerebellum (2003) [Pubmed]
  13. The yeast frataxin homologue mediates mitochondrial iron efflux. Evidence for a mitochondrial iron cycle. Radisky, D.C., Babcock, M.C., Kaplan, J. J. Biol. Chem. (1999) [Pubmed]
  14. Iron toxicity protection by truncated Ras2 GTPase in yeast strain lacking frataxin. Kucej, M., Foury, F. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  15. Mitochondrial control of iron homeostasis. A genome wide analysis of gene expression in a yeast frataxin-deficient strain. Foury, F., Talibi, D. J. Biol. Chem. (2001) [Pubmed]
  16. Acidic residues of yeast frataxin have an essential role in Fe-S cluster assembly. Foury, F., Pastore, A., Trincal, M. EMBO Rep. (2007) [Pubmed]
  17. An interaction between frataxin and Isu1/Nfs1 that is crucial for Fe/S cluster synthesis on Isu1. Gerber, J., Mühlenhoff, U., Lill, R. EMBO Rep. (2003) [Pubmed]
  18. Deletion of the mitochondrial carrier genes MRS3 and MRS4 suppresses mitochondrial iron accumulation in a yeast frataxin-deficient strain. Foury, F., Roganti, T. J. Biol. Chem. (2002) [Pubmed]
  19. Mitochondrial functional interactions between frataxin and Isu1p, the iron-sulfur cluster scaffold protein, in Saccharomyces cerevisiae. Ramazzotti, A., Vanmansart, V., Foury, F. FEBS Lett. (2004) [Pubmed]
  20. J-domain protein, Jac1p, of yeast mitochondria required for iron homeostasis and activity of Fe-S cluster proteins. Kim, R., Saxena, S., Gordon, D.M., Pain, D., Dancis, A. J. Biol. Chem. (2001) [Pubmed]
  21. Biogenesis of the yeast frataxin homolog Yfh1p. Tim44-dependent transfer to mtHsp70 facilitates folding of newly imported proteins in mitochondria. Geissler, A., Krimmer, T., Schönfisch, B., Meijer, M., Rassow, J. Eur. J. Biochem. (2000) [Pubmed]
 
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