ライフサイエンスコーパス: frataxin

1 ess and pathology observed in the absence of frataxin.

2 a genetic disease caused by deficiencies in frataxin.

3 by a deficiency in the mitochondrial protein frataxin.

4 eads to epigenetic modifications and reduced frataxin.

5 processing of cytosolic precursors, such as frataxin.

6 ent oligomers contribute to the functions of frataxin.

7 in the first intron of the gene that encodes frataxin.

8 s transcription leading to the deficiency of frataxin.

9 generative disorder caused by a reduction in frataxin.

10 ure of ferrous iron bound to monomeric yeast frataxin.

11 is caused by decreased levels of the protein frataxin.

12 duced synthesis of the mitochondrial protein frataxin.

13 uced expression of the mitochondrial protein frataxin.

14 and/or function of the mitochondrial protein frataxin.

15 ticed, potential ubiquitin-binding domain in frataxin.

16 of yeast (Yfh1) and Escherichia coli (CyaY) frataxin.

17 nal activities of superoxide dismutase 2 and frataxin, 2 common target genes involved in radical dism

18 eich ataxia is caused by reduced activity of frataxin, a conserved iron-binding protein of the mitoch

19 Frataxin, a conserved nuclear-encoded mitochondrial prot

20 FXN gene, which codes for the 210 amino acid frataxin, a mitochondrial protein involved in iron-sulfu

21 the gene, thus diminishing the synthesis of frataxin, a mitochondrial protein involved in iron-sulfu

22 Frataxin, a mitochondrial protein that is directly invol

23 ch's ataxia (FRDA) is caused by mutations in frataxin, a mitochondrial protein whose function remains

24 fect is made possible by the choice of yeast frataxin, a protein that undergoes cold denaturation abo

25 e functional absence of the FXN gene product frataxin, a protein whose exact function still remains u

26 We investigate this phenomenon by studying frataxin, a protein whose normal function is to facilita

27 caused by a decreased level of expression of frataxin, a putative iron chaperone.

28 Frataxin, a small mitochondrial protein linked to the ne

29 e disease caused by reduced transcription of frataxin, a ubiquitously expressed protein.

30 Mutations in the hydrophobic core of frataxin affected stability whereas surface residue muta

31 Monomeric frataxin also binds to Isu, the scaffold protein require

32 Frataxin amino acids affected by the presence of iron ar

33 Deficiency of frataxin, an essential mitochondrial protein, leads to p

34 Reduced levels of frataxin, an essential protein of as yet unknown functio

35 Here we report on the complex between yeast frataxin and ferrochelatase, the terminal enzyme of heme

36 Interactions between frataxin and ISD11, and frataxin and GRP75 were confirmed by co-immunoprecipitat

37 Interactions between frataxin and ISD11, and frataxin and GRP75 were confirme

38 ss-linking confirmed the interaction between frataxin and ISU in the presence of iron and validated t

39 and whether in vivo the interaction between frataxin and Isu is mediated by adaptor proteins is a ma

40 nd presumably the iron chaperone function of frataxin and its interactions with target proteins.

41 ssion, providing a link between increases in frataxin and neurophysiological function.

42 ding site of CyaY, the bacterial ortholog of frataxin and sits in a cavity close to the enzyme active

43 persulfide, but this step is independent of frataxin and strictly dependent on Isd11.

44 there are two interaction interfaces between frataxin and the ferrochelatase dimer.

45 monstrated that ISD11 co-localized with both frataxin and with mitochondria.

46 In E. cuniculi, the iron (frataxin) and sulphur (cysteine desulphurase, Nfs1) dono

47 lar fold to the mitochondrial iron chaperone frataxin, and it may be involved in iron-sulfur cluster

48 riers with approximately 50% decrease of the frataxin are asymptomatic.

49 but surprisingly the main pools of Isu1 and frataxin are cytosolic, creating a conundrum of how thes

50 ve investigated how these different forms of frataxin are regulated in vivo.

51 a new paradigm for understanding the role of frataxin as a regulator of IscS functions.

52 tes that the ferroxidation reaction controls frataxin assembly and presumably the iron chaperone func

53 ish the levels of both complex formation and frataxin-based activation, whereas ferrous iron further

54 Frataxin binding dramatically changes the K(M) for cyste

55 Frataxin binds Isu in an iron-dependent manner in vitro.

56 These data suggest that frataxin binds the iron-sulfur biogenesis Nfs1/ISCU comp

57 Here we provide in vitro evidence that human frataxin binds to a Nfs1, Isd11, and Isu2 complex to gen

58 Monomeric frataxin binds with high affinity to ferrochelatase, the

59 Nevertheless, derepression of frataxin by a histone deacetylase inhibitor leads to a d

60 nthesized and tested for specific binding to frataxin by an UF-LC/MS based ligand-binding assay.

61 We show that human frataxin can enhance the availability of Fe(II) in monom

62 These results suggest that frataxin can use different molecular forms to accomplish

63 The point mutations I154F and W155R in frataxin cause FRDA and are clustered to one surface of

64 ited deficiency of the mitochondrial protein frataxin causes Friedreich's ataxia (FRDA); the mechanis

65 s, decreased amounts or impaired function of frataxin causes the autosomal recessive neurodegenerativ

66 mitochondrial proteins include mutations of frataxin causing Friedreich's ataxia, PINK1, DJ1 causing

67 ound that Fdx, IscU, and CyaY (the bacterial frataxin) compete for overlapping binding sites on IscS.

68 s associated with a sustained improvement in frataxin concentrations towards those seen in asymptomat

69 This study also suggests that frataxin could be a potential target for FRDA drug devel

70 ng an in vitro disease model, we studied how frataxin deficiency affects beta-cell function and survi

71 thesis that the respiratory chain defects in frataxin deficiency alter mitochondrial protein acetylat

72 dependent, and that multiple consequences of frataxin deficiency are duplicated by ISD11 deficiency.

73 These results suggest that frataxin deficiency causes defects late in the heme path

74 Humans with frataxin deficiency have Friedreich's ataxia, a neurodeg

75 f nicotinamide and its ability to ameliorate frataxin deficiency in Friedreich's ataxia is warranted.

76 Although frataxin is ubiquitously expressed, frataxin deficiency leads to a selective loss of dorsal

77 Collectively, cardiac frataxin deficiency reduces Nrf2 levels via two potentia

78 planation for the elevated oxylipins is that frataxin deficiency results in increased COX activity.

79 Frataxin deficiency sensitized beta cells to oleate-indu

80 ged in cells from patients with pathological frataxin deficiency, and a core set of these genes were

81 eart and skeletal muscle in a mouse model of frataxin deficiency, and found molecular evidence of inc

82 ctor Srebp1 in cellular and animal models of frataxin deficiency, and in cells from FRDA patients, wh

83 a neurodegenerative disorder resulting from frataxin deficiency, is thought to involve progressive c

84 s known that DRG are inherently sensitive to frataxin deficiency, recent observations also indicate t

85 nherited neurodegenerative disease caused by frataxin deficiency.

86 ion of this pathway could play a key role in frataxin deficiency.

87 iodegenerative disease resulting from marked frataxin deficiency.

88 eration is due to the sensitivity of DRGs to frataxin deficiency; however, the progressive nature of

89 ning all mouse and human microarray data for frataxin-deficient cells and tissues, the most consisten

90 n potentially further compromise function in frataxin-deficient cells by decreasing frataxin expressi

91 me deficiency, the heme defect we observe in frataxin-deficient cells could be primary to the pathoph

92 inferred cytosolic iron depletion occurs as frataxin-deficient cells overload their mitochondria wit

93 Frataxin-deficient mice, which had higher mitochondrial

94 We propose that pathology in the frataxin-deficient nervous system involves decreased MMP

95 These findings are in contrast to the frataxin-deficient skeletal muscle, where Nrf2 was not d

96 which the expanded repeats contribute to the frataxin deficit in FRDA.

97 s, expression of partially functional mutant frataxin delays age of onset and reduces diabetes mellit

98 e that mirrors the disease have demonstrated frataxin deletion alters cardiac Fe metabolism.

99 A conditional mouse model with complete frataxin deletion in cardiac and skeletal muscle (Mck-Cr

100 Namely, frataxin deletion induces a signaling mechanism to incre

101 effect of heart and skeletal muscle-specific frataxin deletion on systemic Fe metabolism.

102 ve shown that either monomeric or oligomeric frataxin delivers iron to other proteins, whereas ferrit

103 This novel function of frataxin does not require iron, Isu1, or Isd11.

104 Frataxin downregulation is associated with robust change

105 ynthesis of the mitochondrial iron chaperone frataxin due to impaired gene transcription, which leads

106 ere show that the Isu1 suppressor mimics the frataxin effects on Nfs1, explaining the bypassing activ

107 d to associate with the iron binding protein frataxin exclusively during reperfusion.

108 Moreover, later administration of the frataxin-expressing vector, after the onset of heart fai

109 In Drosophila larvae with reduced frataxin expression (DfhIR), we evaluated possible mecha

110 view on articles pertaining to activation of frataxin expression (Friedreich's ataxia) and production

111 ferent cells and tissues, and its effects on frataxin expression are not yet completely understood.

112 our study, we investigated the regulation of frataxin expression by iron and demonstrated that fratax

113 Alterations up or down of frataxin expression caused compensatory changes in HSC20

114 diabetes mellitus, compared to those with no frataxin expression from the non-expanded allele.

115 s cytosolic iron levels to maximize residual frataxin expression in FA patients.

116 n across repressive GAA repeats that silence frataxin expression in Friedreich's ataxia, a terminal n

117 ic Fe levels and Fe loading in tissues where frataxin expression is intact (i.e., liver, kidney, and

118 indicate that approaches aimed to reactivate frataxin expression should simultaneously address defici

119 orrelated with cytokine-induced increases in frataxin expression, providing a link between increases

120 d and significant (p<0.0001) upregulation of frataxin expression, which was accompanied by a reductio

121 ogenesis of the disease) and a regulators of frataxin expression.

122 on in frataxin-deficient cells by decreasing frataxin expression.

123 XN gene causes Friedreich ataxia by reducing frataxin expression.

124 ic modifications of the FXN gene to increase frataxin expression.

125 ur in 96% of affected individuals and reduce frataxin expression.

126 ene leading to transcriptional repression of frataxin expression.

127 The primary outcome was the upregulation of frataxin expression.

128 lts show a continuous compaction of unfolded frataxin from 274 to 320 K, with a slight re-expansion a

129 The ability of frataxin from different organisms to populate multiple o

130 us exists on the details of the mechanism of frataxin function and oligomerization.

131 understanding of the mechanistic features of frataxin function requires detailed knowledge of the int

132 Most researchers agree that frataxin functions in the biogenesis of Fe-S clusters, b

133 Together, these results indicate human frataxin functions with Fe(2+) as an allosteric activato

134 nt mutation in Isu1 was found to bypass many frataxin functions.

135 Mutations in Frataxin (FXN) cause Friedreich's ataxia (FRDA), a reces

136 ited deficiency in the mitochondrial protein frataxin (FXN) causes the rare disease Friedreich's atax

137 GAA . TTC repeat in the first intron of the frataxin (FXN) gene causes an mRNA deficit that results

138 Expanded GAA repeats within intron 1 of the frataxin (FXN) gene lead to its heterochromatinisation a

139 n of an intronic trinucleotide repeat in the frataxin (FXN) gene yielding diminished FXN expression a

140 enerative disease caused by mutations in the frataxin (FXN) gene, resulting in reduced expression of

141 onic GAA.TTC triplet repeat expansion in the frataxin (FXN) gene.

142 ding to the transcriptional silencing of the frataxin (FXN) gene.

143 ditary ataxia, is caused by mutations in the frataxin (FXN) gene.

144 elated with the number of GAA repeats in the frataxin (FXN) gene: every 100 GAA repeats on the smalle

145 edreich's ataxia (FRDA) patients, diminished frataxin (FXN) in sensory neurons is thought to yield th

146 his expansion leads to reduced expression of frataxin (FXN) protein and evidence suggests that transc

147 ted with the loss of function of the protein frataxin (FXN) that results from low FXN levels due to a

148 ecessive mutations that reduce the levels of frataxin (FXN), a mitochondrial iron binding protein.

149 disease caused by insufficient expression of frataxin (FXN), a mitochondrial iron-binding protein req

150 FRDA is caused by reduced levels of frataxin (FXN), an essential mitochondrial protein invol

151 and associates with assembly proteins ISCU2, frataxin (FXN), and ferredoxin to synthesize Fe-S cluste

152 ysteine desulfurase complex (NFS1/ISD11) and frataxin (FXN), the protein deficient in Friedreich's at

153 ited deficiency of the mitochondrial protein Frataxin (FXN), which has no approved therapy and is an

154 ne normally encodes the iron-binding protein frataxin (FXN), which is critical for mitochondrial iron

155 m a deficiency of the mitochondrial protein, frataxin (FXN), which is encoded in the nucleus.

156 odegenerative disease caused by mutations in Frataxin (FXN).

157 TTC) cause transcriptional repression of the Frataxin gene (FXN) leading to Friedreich's ataxia (FRDA

158 DA), expanded GAA repeats in intron 1 of the frataxin gene (FXN) reduce FXN mRNA levels in averaged c

159 d by large GAA expansions in intron 1 of the frataxin gene (FXN), which lead to reduced FXN expressio

160 A repeat length on the smaller allele of the frataxin gene (hazard ratio [HR], 1.85; 95% CI, 1.28-2.6

161 thetic ligands increase transcription of the frataxin gene in cell culture, resulting in increased le

162 engths that are found in the sequence of the frataxin gene in patients.

163 GAA)n repeats within the first intron of the frataxin gene reduce its expression, resulting in a here

164 nerative disorder caused by mutations in the frataxin gene that produces a predominantly mitochondria

165 The C. elegans frataxin gene, frh-1, is encoded in the operon CEOP2232.

166 the (GAA)n repeat in the first intron of the frataxin gene.

167 a GAA trinucleotide repeat expansion in the frataxin gene.

168 TC triplet repeat in the first intron of the frataxin gene.

169 d products of human disease genes, including frataxin, GLRX5, ISCU, and ABCB7, have important roles i

170 In vitro, frataxin has been shown to protect aconitase from [4Fe-4

171 e physiologic role of iron detoxification by frataxin has not yet been demonstrated in vivo.

172 either single monomers or polymers of human frataxin have been shown to serve as donors of Fe(II) to

173 We show that loss of frataxin homolog (fh) in Drosophila leads to iron toxici

174 We recently showed that loss of frataxin homolog (fh), a Drosophila homolog of FXN, caus

175 ed mitochondria, we show here that the yeast frataxin homolog (Yfh1) directly and specifically stimul

176 ase serving as a sulfur donor, and the yeast frataxin homolog (Yfh1) serving as a regulator of desulf

177 Deletion of the yeast frataxin homolog (YFH1) was combined with deletions of M

178 We have identified a frataxin homolog in fission yeast, and we have analyzed

179 The cyaY locus encodes a frataxin homolog, and it is shown here that lesions in t

180 nd iron binding properties of the Drosophila frataxin homologue (Dfh).

181 ex consisting of the iron donor, Yfh1 (yeast frataxin homologue 1), and the Fe-S cluster scaffold, Is

182 We also show that like frataxin, HSC20 interacts with multiple proteins involve

183 rescued the defective interaction of mutant frataxin I154F and W155R with ISD11.

184 er scaffold and point to a critical role for frataxin in Fe-S cluster biogenesis.

185 The role of the mitochondrial protein frataxin in iron storage and detoxification, iron delive

186 acts with the Friedreich ataxia gene product frataxin in iron-sulfur cluster biosynthesis.

187 tified multiple interactors of mitochondrial frataxin in mammalian cells.

188 imum activity as follows: one is mediated by frataxin interaction that exposes the "buried" substrate

189 e developed a model for how we believe yeast frataxin interacts with iron.

190 Frataxin interacts with Isu, iron, and the cysteine desu

191 Previously we demonstrated that frataxin interacts with multiple components of the mamma

192 Biochemical and genetic studies have shown frataxin interacts with the iron-sulfur cluster assembly

193 Here we demonstrate that frataxin interacts with the mammalian mitochondrial chap

194 Import of frataxin into frataxin-minus isolated mitochondria promp

195 Frataxin is a conserved mitochondrial protein implicated

196 Frataxin is a conserved mitochondrial protein that contr

197 Frataxin is a conserved mitochondrial protein that plays

198 Frataxin is a mitochondrial iron-binding protein involve

199 Frataxin is a mitochondrial protein involved in iron hom

200 Despite the fact that frataxin is an essential gene, its promoter is not well

201 Cellular depletion of the human protein frataxin is correlated with the neurodegenerative diseas

202 Here, we report findings that frataxin is degraded via the ubiquitin-proteasomal pathw

203 Frataxin is implicated in the process, although it is un

204 Thus, the role of frataxin is not limited to promoting ISC assembly or hem

205 Although frataxin is nuclear-encoded, it is targeted to the mitoc

206 Frataxin is required for the cellular production of both

207 Yeast frataxin is stable as an iron-loaded monomer, and the pr

208 Frataxin is thought to transiently interact with ISU, th

209 Although frataxin is ubiquitously expressed, frataxin deficiency

210 The frataxin/ISD11 interaction was also decreased by the che

211 A theoretical model of the frataxin-K(147)/Ub complex, constructed by combining bio

212 RNA interference-mediated frataxin knockdown impaired glucose-stimulated insulin s

213 Using a mouse conditional frataxin knockout (KO) model in the heart and skeletal m

214 using the muscle creatine kinase conditional frataxin knockout (KO) mouse; this mouse develops a seve

215 the muscle creatine kinase (MCK) conditional frataxin knockout mouse that mirrors the disease have de

216 Frataxin KO results in fatal cardiomyopathy, whereas ske

217 rt the hypothesis that reduced expression of frataxin leads to elevation of COX2-mediated oxylipin sy

218 Both G-CSF and SCF had pronounced effects on frataxin levels (the primary molecular defect in the pat

219 modulation of the PPARgamma pathway affects frataxin levels in vitro, supporting PPARgamma as a nove

220 We propose a model in which cellular frataxin levels regulate human Fe-S cluster biosynthesis

221 for developing therapies aimed at increasing frataxin levels to treat this debilitating disease.

222 nd expanded FXN loci with rapid detection of frataxin levels.

223 vitro treatment with compounds that increase frataxin levels.

224 SUD-C adopts a frataxin like fold and has structural similarity to DNA-

225 ed at preventing the debilitating effects of frataxin loss and preventing the signs and symptoms asso

226 ndings observed in FXTAS cells (lower mature frataxin, lower Complex IV and aconitase activities) alo

227 p transports iron into mitochondria, whereas frataxin makes iron already within mitochondria availabl

228 Because frataxin may participate in transient interactions with

229 urea] 50% approximately 2.4 M) of Drosophila frataxin, measured using circular dichroism (CD) and flu

230 Frataxin measurements from peripheral tissues can be use

231 Furthermore, they support the proposal that frataxin-mediated delivery of this potentially toxic sub

232 Finally, frataxin mediates the delivery of Fe(II) to Isu, promoti

233 irements for iron, suggesting that monomeric frataxin might function as the common iron donor.

234 Import of frataxin into frataxin-minus isolated mitochondria promptly corrected

235 urements demonstrated that in the absence of frataxin, mitochondria contained biomineral Fe aggregate

236 Deficiency of the frataxin mRNA alters the transcriptome, triggering neuro

237 rataxin show comparatively reduced levels of frataxin mRNA and protein expression, decreased aconitas

238 In addition, frataxin mRNA and protein levels decrease in fibroblast

239 xin expression by iron and demonstrated that frataxin mRNA levels decrease significantly in multiple

240 lity and in the mechanism underlying reduced frataxin mRNA levels in Friedreich Ataxia.

241 The frataxin mutant strain lacked protein import capacity be

242 This integrated analysis of categorized frataxin mutations and their correlation with clinical o

243 Frataxin mutations were examined using structural modeli

244 How frataxin normally promotes survival of these particular

245 We have proposed that frataxin not only promotes the biogenesis of iron-contai

246 estigates the participation of the bacterial frataxin ortholog CyaY and the YggX protein, which are p

247 ed the iron binding property of IscA and the frataxin ortholog CyaY from Escherichia coli under physi

248 nsistent with the structurally characterized frataxin orthologs.

249 d strand 1 in the structurally characterized frataxin orthologs.

250 ron to other proteins, whereas ferritin-like frataxin particles convert redox-active iron to an inert

251 t, there are two, Isu1 and Isu2), indicating frataxin plays a direct role in cluster assembly, possib

252 The mitochondrial protein frataxin plays a key role in these processes by a novel

253 Our data indicate that frataxin point mutations have complex biochemical effect

254 Frataxin prevents reactive oxygen species-induced oxidat

255 e compound heterozygote groups; (2) null (no frataxin produced); (3) moderate/strong impact; and (4)

256 by blocking binding of factors that increase frataxin promoter activity.

257 exists to ameliorate symptoms by increasing frataxin promoter activity.

258 Most of the activity of the human frataxin promoter can be attributed to these retroelemen

259 We therefore defined the minimal frataxin promoter in humans.

260 response relation for proportional change in frataxin protein concentration from baseline to 8 h post

261 .5-times increase and 7.5 g in a doubling of frataxin protein concentration.

262 Higher P:M, and lower ZnT6 and mature frataxin protein expression suggested defective zinc and

263 ecreased transcription and reduced levels of frataxin protein in affected individuals.

264 Frataxin protein levels from multiple cell types in cont

265 ffects as well as for increases in FXN mRNA, frataxin protein, and chromatin modification in blood ce

266 ACi 109/RG2833 increases FXN mRNA levels and frataxin protein, with concomitant changes in the epigen

267 e FXN gene, leading to reduced expression of frataxin protein.

268 ll culture, resulting in increased levels of frataxin protein.

269 erative disorder caused by deficiency of the frataxin protein.

270 table monomeric and assembled forms of human frataxin purified from Escherichia coli have provided a

271 The degree of frataxin reduction correlates with GAA.TTC tract length,

272 Iron detoxification is another function of frataxin relevant to anti-oxidant defense and cell longe

273 Defects in frataxin result in Friedreich ataxia, a genetic disease

274 Loss of frataxin results in mitochondrial dysfunction and oxidat

275 ovide a molecular basis to better understand frataxin's function, we have characterized the binding p

276 nt FRDA mice that express only human-derived frataxin show comparatively reduced levels of frataxin m

277 e results indicate that HSC20 interacts with frataxin structurally and functionally and is important

278 disease-causing mutations and the impact on frataxin structure/function and clinical outcome in FRDA

279 The predominant view is that frataxin sustains mitochondrial energy production and ot

280 ken together, these results indicate that in frataxin the competition between folding and function cr

281 eserved, whereas mRNA and protein levels for frataxin, the oxidative stress-regulated mitochondrial a

282 s mutation impacts the maturation process of frataxin, the protein which is depleted in Friedreich at

283 Independent reports have linked frataxin to iron-sulphur cluster assembly through intera

284 controlled fashion and that this may enable frataxin to simultaneously promote respiratory function

285 involves one ferrochelatase monomer and one frataxin trimer, with conserved polar and charged amino

286 s with micromolar activity in disrupting the frataxin/Ub interaction.

287 l molecule (compound (+)-11) able to prevent frataxin ubiquitination and degradation.

288 Higher P:M of ATPase beta-subunit (ATPB) and frataxin were also observed in cortex from patients that

289 xidation or mineralization activity of yeast frataxin, which are necessary for iron detoxification bu

290 conserved, surface-exposed residues of yeast frataxin, which have deleterious effects on cell growth,

291 Frataxin, which is significantly reduced in patients wit

292 sed expression of the mitochondrial protein, frataxin, which leads to alterations in mitochondrial ir

293 we investigated the unfolded state of yeast frataxin, whose cold denaturation occurs at temperatures

294 these mutations decrease the interaction of frataxin with ISD11.

295 raction of CyaY (the bacterial orthologue of frataxin) with the IscS/IscU complex.

296 re we provide molecular details of how yeast frataxin (Yfh1) interacts with Isu1 as a structural modu

297 ccharomyces cerevisiae, only monomeric yeast frataxin (Yfh1) was detected in unstressed cells when mi

298 s similar to that which accumulates in yeast frataxin Yfh1p-deleted or yeast ferredoxin Yah1p-deplete

299 Yeast frataxin (Yfh1p), the homolog of the human protein impli

300 rs4p mitochondrial carriers and iron-binding frataxin (Yfh1p).