ライフサイエンスコーパス: CypD

1 CypD activity also correlated with synthasome assembly i

2 CypD enhances the limiting effect of Bcl2 on the tBid-in

3 CypD is hypothesized to trigger mPTP opening through iso

4 CypD knockout mice also presented accelerated wound heal

5 CypD loss triggers a metabolic shift in Ppif-/- male and

6 CypD was upregulated in HD patients, and this upregulati

7 CypD(-/-) mice developed a less-severe form of pancreati

8 CypD-deficient platelets exhibited defects in phosphatid

9 CypD-deficient primary mouse embryonic fibroblasts (MEFs

10 CypD-dependent proteolytic events, including cleavage of

11 the role of CypD in cell death, we created a CypD-deficient mouse.

12 platelets and initiating subsequent PA in a CypD- and TMEM16F-dependent manner both in vivo and in v

13 ion, and platelet procoagulant activity in a CypD-dependent manner.

14 yclophilin D), suggesting the existence of a CypD-independent mechanism for ROS sensitization of the

15 This activates CypD's isomerase activity.

16 he reported role of CypD in mPTP activation, CypD null (CypD(-/-)) MEFs exhibited significantly less

17 Our study finds that catalytically active CypD causes strong aggregation of wild-type p53 protein

18 nd Ppif(-/-) mice (indicating an additional, CypD-independent effect on mPTP opening) and in primary

19 tors of cyclophilins and tested them against CypD using binding and isomerase activity assays.

20 Tomm40 (translocase of outermembrane 40) and CypD (cyclophilin D) in grade III and grade IV HD patien

21 study provides direct evidence that ANT1 and CypD are required MPTP components governing in vivo cell

22 The increase in Drp1, Fis1 and CypD and the decrease in Mfn1 and Mfn2 may be responsibl

23 rotein levels of Drp1 and Fis1 (fission) and CypD (matrix) genes, and increased levels of Mfn1, Mfn2

24 the regulation of mitochondrial function and CypD expression is still unclear.

25 ion of the dynamic interface between NTD and CypD provides novel insights on the p53-dependent mPTP o

26 bility transition pore opening in a p53- and CypD-dependent manner.

27 igomeric complex composed of VDAC, SPG7, and CypD.

28 ls of pancreatitis, induced in wild-type and CypD(-/-) mice by a combination of ethanol and CCK.

29 ated cardiac mitochondria from wild-type and CypD(-/-) mice to immunoprecipitation using agarose bead

30 ptides that were acetylated in wild-type and CypD(-/-) samples and found 11 peptides (10 proteins) de

31 d heart mitochondria from wild-type (WT) and CypD knockout (KO) mice were treated to either stimulate

32 ttenuated by knockdown or inhibition of ANT, CypD, or MCU, and occurred independently of TP53 and p21

33 We investigated the ANT/CypD relationship in mPTP dynamics and I/R injury.

34 rotective chaperone network that antagonizes CypD-dependent cell death in tumors.

35 strate a redox-sensitive interaction between CypD and Mia40, which was further confirmed by co-immuno

36 poxia-reoxygenation, the interaction between CypD and the IP3R1 Ca(2+) channeling complex increased c

37 n2 similarly reduced the interaction between CypD and the IP3R1 complex and protected against hypoxia

38 esidues 22-44) and D2 (58-70), can each bind CypD with mM affinity.

39 on and MD simulation revealed that NTD binds CypD with broad and dynamic interfaces dominated by elec

40 In solution NMR, NTD binds CypD with muM affinity and mimics the pattern of FLp53 b

41 t a new class of non-toxic and biocompatible CypD inhibitor, ebselen, using a conventional PPIase ass

42 The most potent inhibitor (C31) bound CypD with high affinity and inhibited swelling in mitoch

43 f peptidyl-prolyl isomerisation catalysed by CypD.

44 of the F1F0 ATP synthase-CypD interaction by CypD ablation protected against diabetes-induced mPTP op

45 ion, we infected CypD(-/-) MEFs with a C203S-CypD vector.

46 cted a recombinant adenovirus encoding C203S-CypD or WT CypD into CypD(-/-) mice via tail vein.

47 s of CypD(-/-) mice or mice expressing C203S-CypD were resistant to Ca(2+)-induced swelling as compar

48 To determine whether mutation of C203S-CypD would alter mPTP in vivo, we injected a recombinant

49 Surprisingly, C203S-CypD reconstituted MEFs were resistant to mPTP opening i

50 000 drug-like macrocycles for cyclophilin D (CypD) affinity.

51 cally verified regulators are cyclophilin D (CypD) and the adenine nucleotide translocase (ANT) famil

52 e the mitochondrial chaperone cyclophilin D (CypD) and trigger permeability transition pore opening,

53 Cyclophilin D (CypD) appears to be a critical component of the PTP.

54 ER-000444793 neither affected cyclophilin D (CypD) enzymatic activity, nor displaced of CsA from CypD

55 Cyclophilin D (CypD) is a mitochondrial immunophilin and a key positive

56 Cyclophilin D (CypD) is a mitochondrial matrix peptidyl-prolyl isomeras

57 Cyclophilin D (CypD) is a mitochondrial protein that facilitates openin

58 Cyclophilin D (CypD) is a peptidyl-prolyl isomerase expressed in the nu

59 While Cyclophilin D (CypD) is a well-characterized regulator of the mitochond

60 mitochondrial matrix protein cyclophilin D (CypD) is an essential component of the mitochondrial per

61 mitochondrial matrix protein cyclophilin D (CypD) prevents perinatal KET-induced increases in ROS an

62 ity transition pore regulator cyclophilin D (CypD) promotes NGSIS, but not glucose-stimulated insulin

63 Cyclophilin D (CypD) promotes opening of the mitochondrial permeability

64 le within ATP synthase is the cyclophilin D (CypD) regulated mitochondrial permeability transition po

65 mitochondrial matrix protein cyclophilin D (CypD) show robust protection from PVI dysfunction follow

66 t that requires the chaperone cyclophilin D (CypD) to activate.

67 p60) directly associates with cyclophilin D (CypD), a component of the mitochondrial permeability tra

68 Cells deficient in cyclophilin D (CypD), a component of the MPTP, are resistant to MPTP op

69 ve shown that cysteine 203 of cyclophilin D (CypD), a critical mPTP mediator, undergoes protein S-nit

70 d at inhibiting mitochondrial cyclophilin D (CypD), a key regulator of the mPT, as a potential therap

71 platelet-specific deletion of cyclophilin D (CypD), a mediator of necrosis, we found that platelet ne

72 he mitochondrial MAM protein, cyclophilin D (CypD), altered insulin signaling in mouse and human prim

73 In the absence of cyclophilin D (CypD), an essential regulator of MPTP formation, murine

74 permeability transition pore, cyclophilin D (CypD), influenced endothelial metabolism and intracellul

75 the peptidyl-prolyl isomerase cyclophilin D (CypD), mortalin decreased mitochondrial permeability by

76 nucleotide translocase (ANT), cyclophilin D (CypD), or mitochondrial Ca(2+) uniporter (MCU), which im

77 Cyclophilin D (CypD), the peptidylprolyl isomerase F (PPIase), is a key

78 ingle-channel patch clamp and cyclophilin D (CypD)-deficient mice (Ppif (-/-)) with streptozotocin-in

79 report an unexplored role of cyclophilin D (CypD)-dependent mitochondrial permeability transition po

80 is impaired in the absence of cyclophilin D (CypD).

81 action with the PTP regulator cyclophilin D (CypD).

82 tivates the key mPT regulator cyclophilin D (CypD).

83 pore permeability regulator, Cyclophilin D (CypD).

84 or reduction in the levels of cyclophilin D (CypD, also called Ppif), a mitochondrial matrix peptidyl

85 Cyclophilin D (CypD, encoded by Ppif) is an integral part of the mitoch

86 Ca(2+) retention, similar to cyclophilin D (CypD, PPIF) knockdown with sustained DeltaPsim during bo

87 The peptidylprolyl isomerase, cyclophilin D (CypD, PPIF), is a positive regulator of the pore, and ge

88 However, there is currently no effective CypD inhibitor for Alzheimer's disease, with previous ca

89 Platelet-specific genetic loss of either CypD or TMEM16F as well as combined blockade of platelet

90 Inhibition of either CypD, IP3R1, or Grp75 decreased protein interaction with

91 resent a new proline isomerization assay for CypD by monitoring the aggregation of p53 as an indicato

92 type, indicating that P62 is dispensable for CypD regulation.

93 previously unrecognized import mechanism for CypD and expand the known substrate repertoire of Mia40,

94 identified as the minimal binding region for CypD interaction, and two NTD fragments, D1 (residues 22

95 n, strongly supporting an essential role for CypD in an ischemic injury model in which calcium overlo

96 These results implicate a role for CypD in modulating protein acetylation.

97 nzymatic activity, nor displaced of CsA from CypD protein, suggesting a mechanism independent of CypD

98 ent endothelial cells and aortic tissue from CypD knockout mice exhibited a dramatic increase in angi

99 Functionally, CypD-deficient endothelial cells and aortic tissue from

100 is1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis-Nrf1, Nrf2, PGC1

101 The matrix gene CypD was up-regulated in AD patients.

102 We, therefore, generated CypD-RIPK3 double-deficient mice that are viable and fer

103 s from hypertensive patients had 280% higher CypD acetylation coupled with reduced Sirt3 (sirtuin 3)

104 iabetic obese mice show significantly higher CypD-dependent proton leak and NGSIS compared with lean

105 However, CypD-deficient MEFs were significantly less susceptible

106 In this study, we identify CypD as a novel non-canonical substrate of the mitochond

107 These results implicate CypD and the MPTP as critical regulators of platelet act

108 th induced by hydrogen peroxide, implicating CypD in oxidative stress-induced cell death.

109 Importantly, CypD-deficient mice displayed a dramatic reduction in br

110 jury, thrombosis was markedly accelerated in CypD-deficient mice.

111 Also, in CypD-deficient platelet-rich plasma, clot retraction was

112 ht play a role in these metabolic changes in CypD(-/-) hearts.

113 d and 96 peptides (48 proteins) increased in CypD(-/-) samples.

114 ibute to altered mitochondrial metabolism in CypD(-/-) mice.

115 sed synthasome disassembly in WT, but not in CypD KO heart mitochondria.

116 ed by MPTP because they were not observed in CypD(-/-) acinar cells.

117 nalysis revealed conserved cysteine pairs in CypD that are compatible with disulfide bond formation.

118 id oxidation that was previously reported in CypD(-/-) hearts, we measured the activity of l-3-hydrox

119 study, we observed that BMSCs have increased CypD expression and MPTP activity, activated glycolysis,

120 is required for this protection, we infected CypD(-/-) MEFs with a C203S-CypD vector.

121 The resulting macrocycles inhibit CypD activity with 21- to >10,000-fold selectivity over

122 indirectly activates the normally inhibited CypD by displacing it from Trap1 complexes.

123 bility transition pore opening by inhibiting CypD activity is a promising therapeutic approach for Al

124 enovirus encoding C203S-CypD or WT CypD into CypD(-/-) mice via tail vein.

125 These findings provide new insights into CypD-dependent mitochondrial mPTP and signaling on mitoc

126 hanisms of the protective effects of lacking CypD on Abeta-induced abnormal mitochondrial transport i

127 Liberated CypD then isomerizes multiple proteins including p53 (ca

128 Thus, instead of DBD, NTD is the major CypD binding site on p53.

129 Deacetylation mimetic CypD-K166R mice were protected from vascular oxidative s

130 of CypD acetylation in deacetylation mimetic CypD-K166R mutant mice and endothelial-specific GCN5L1 (

131 to a significant reduction in mitochondrial CypD levels, a result that was confirmed in a series of

132 pothesized that acetylation of mitochondrial CypD (cyclophilin D) at K166 contributes to endothelial

133 Similarly, genetic ablation of mitochondrial CypD in Ppif-null mice did not afford protection from AP

134 In summary, loss of mitochondrial CypD results in a shift in bioenergetics and in activati

135 ury in livers of mice given a small-molecule CypD inhibitor or vehicle before and during reperfusion

136 The effects of the small-molecule CypD inhibitors or vehicle on mPTP opening were assessed

137 of a nitric oxide donor, GSNO, to WT but not CypD(-/-) MEFs prior to H(2)O(2) attenuated mPTP opening

138 Notably, CypD deficiency substantially improves learning and memo

139 bbeta3 inactivation, and demonstrate a novel CypD-dependent negative feedback mechanism that limits p

140 s of platelet activation and suggest a novel CypD-dependent negative-feedback mechanism regulating ar

141 Here we identified a novel, CypD-independent inhibitor of the mPTP.

142 PTP opening and drug discovery targeting NTD/CypD interface in diseases.

143 role of CypD in mPTP activation, CypD null (CypD(-/-)) MEFs exhibited significantly less mPTP openin

144 mPTP activation, we mutated cysteine 203 of CypD to a serine residue (C203S) and determined its effe

145 ther, these results suggest that ablation of CypD leads to changes in the mitochondrial acetylome, wh

146 d to map acetylation sites after ablation of CypD, we subjected tryptic digests of isolated cardiac m

147 uced mPTP opening persists in the absence of CypD (cyclophilin D), suggesting the existence of a CypD

148 Furthermore, the absence of CypD alleviated deficits in synaptic plasticity, learnin

149 Furthermore, the absence of CypD protects neurons from Abeta- and oxidative stress-i

150 In the absence of CypD, active STAT3 enhances cell proliferation via accel

151 In the absence of CypD, integrin alphaIIbbeta3 function was accentuated in

152 not be critically involved in the absence of CypD.

153 d cell injury predominates in the absence of CypD.

154 The synergistic activation of CypD by C/EBPalpha and the NF-kappaB p65 subunit during

155 C/EBPalpha as a transcriptional activator of CypD.

156 Furthermore, the addition of CypD to preformed alphaSyn fibrils leads to the disassem

157 le inhibitors of cyclophilins in an assay of CypD activity.

158 Blockade of CypD may be a therapeutic strategy in Alzheimer's diseas

159 s of genetic and pharmacological blockade of CypD on Alzheimer's disease mitochondrial and glycolytic

160 bute to malignant traits under conditions of CypD modulation.

161 mice with a platelet-specific deficiency of CypD.

162 Deletion of CypD also prevented KET-induced behavioral deficits in c

163 XPHOS, inhibition of the PTP, or deletion of CypD increased high order synthasome assembly.

164 bly, blockade of mPTP by genetic deletion of CypD suppresses Abeta-mediated activation of the p38 mit

165 cological inhibition or genetic depletion of CypD and that peroxynitrite-mediated cell injury predomi

166 Depletion of CypD significantly protects axonal mitochondrial motilit

167 models in mice suggested the distinctness of CypD-mediated MPT from RIPK1/RIPK3-mediated necroptosis.

168 ation is evidenced by the negative effect of CypD 'rescue' via gain-of-function on osteogenesis both

169 from mitochondria and that such an effect of CypD is cyclosporine A- and Bcl2-dependent.

170 pothesized that the anti-apoptotic effect of CypD is independent of the MPT but is due to its interac

171 Here we characterized the effects of CypD ablation on bioenergetics in the kidney.

172 Diabetes-induced elevation of CypD triggers enhancement of F1F0 ATP synthase-CypD inte

173 Expression of CypD cysteine mutants in cells revealed that residues Cy

174 refore, we here describe a novel function of CypD as a Bcl2 collaborator and an inhibitor of cytochro

175 This function of CypD may explain the anti-apoptotic effect of this prote

176 otein, suggesting a mechanism independent of CypD inhibition.

177 contributes to mPTP opening independently of CypD.

178 ng the aggregation of p53 as an indicator of CypD activity.

179 on revealed selective cellular inhibition of CypD and the permeability transition pore with reduced c

180 Inhibition of CypD by ebselen protects against sporadic Alzheimer's di

181 Genetic or pharmacological inhibition of CypD in both H9c2 cardiomyoblasts and adult cardiomyocyt

182 Genetic or pharmacological inhibition of CypD provided a similar effect in adult mice cardiomyocy

183 ecently created small-molecule inhibitors of CypD prevent opening of the mPTP in hepatocytes and the

184 ecently created small-molecule inhibitors of CypD reduced calcium-induced swelling in mitochondria fr

185 Here we show that interaction of CypD with mitochondrial amyloid-beta protein (Abeta) pot

186 llular level, overexpression or knockdown of CypD respectively decreases or increases cytochrome c re

187 Mitochondria isolated from livers of CypD(-/-) mice or mice expressing C203S-CypD were resist

188 aim was to test the hypothesis that loss of CypD alters the cardiac mitochondrial acetylome.

189 Mice with loss of CypD in platelets (CypDplt-/-mice) exhibited significant

190 kt were also noted in the aorta and lungs of CypD knockout mice.

191 Enzymatically-compromised mutants of CypD show reduced abilities to dissociate alphaSyn aggre

192 ing at the putative ligand binding pocket of CypD.

193 terized BMP/Smad signaling as a regulator of CypD expression and elucidated the role of CypD downregu

194 results indicate that the Cys-203 residue of CypD is necessary for redox stress-induced activation of

195 l hypertension, defined a pathogenic role of CypD acetylation in deacetylation mimetic CypD-K166R mut

196 These data support the pathogenic role of CypD acetylation in endothelial dysfunction and hyperten

197 Our data (1) point to a new role of CypD at the ER-mitochondria interface and (2) suggest th

198 f CypD expression and elucidated the role of CypD downregulation during cell differentiation.

199 To investigate the role of CypD in cell death, we created a CypD-deficient mouse.

200 Consistent with the reported role of CypD in mPTP activation, CypD null (CypD(-/-)) MEFs exhi

201 nuates loss of synapse, suggesting a role of CypD-dependent signaling in Abeta-induced alterations in

202 There are, however, other possible roles of CypD in the mitochondria which may or may not be linked

203 C(50)) = 10 nM) that bind the active site of CypD and also make novel interactions with non-conserved

204 en new high-resolution crystal structures of CypD-inhibitor complexes were obtained to guide compound

205 uman endothelial cells, genetic targeting of CypD using siRNA or shRNA resulted in a constitutive inc

206 kout mice was significantly stronger than of CypD-deficient mice.

207 d human primary hepatocytes and treatment of CypD knockout mice with metformin improved both insulin

208 Cyclophilin D (PPIF or CypD) is a peptidyl-prolyl cis-trans isomerase that regu

209 deleting the gene encoding ANT1 (Slc25a4) or CypD (Ppif) in a delta-sarcoglycan (Sgcd) gene-deleted m

210 The fact that some tumors overexpress CypD suggests that this may be an additional mechanism o

211 reasing organelle contacts by overexpressing CypD enhanced insulin action in primary hepatocytes of d

212 Our study identifies the mitochondrial p53-CypD axis as an important contributor to oxidative stres

213 Intriguingly, a robust p53-CypD complex forms during brain ischemia/reperfusion inj

214 However, the molecular details of p53/CypD interaction are still poorly understood.

215 ot compromise hemostasis, targeting platelet CypD may be a potential therapeutic strategy to limit br

216 ria from C57BL/6J (wild-type) and Ppif(-/-) (CypD knockout) mice and in primary mouse and human hepat

217 tochondrial protein acetylation and promotes CypD acetylation, which is counteracted by mitochondrial

218 50% increase in GCN5L1/Sirt3 ratio promoting CypD acetylation.

219 HOBA) normalized GCN5L1/Sirt3 ratio, reduced CypD acetylation, and attenuated hypertension.

220 chondrial isolevuglandins and GCN5L1 reduces CypD acetylation, which may be beneficial in cardiovascu

221 re, beneficial for cells to tightly regulate CypD and MPTP but little is known about such regulation.

222 The responsible CypD residues for this activity were mapped by NMR to th

223 These findings suggest that selective CypD inhibition may represent a viable therapeutic strat

224 prevented by cotreatment with the selective CypD inhibitor, Debio 025 (alisporivir, DEB025, a nonimm

225 Downstream of SIRT1, CypD-deficient endothelial cells exhibited reduced phosp

226 Silencing or disruption of SPG7-CypD binding prevented Ca(2+)- and ROS-induced DeltaPsim

227 To test this hypothesis, we studied CypD acetylation in patients with essential hypertension

228 The importance of such CypD downregulation is evidenced by the negative effect

229 Notably, blockade of the F1F0 ATP synthase-CypD interaction by CypD ablation protected against diab

230 pD triggers enhancement of F1F0 ATP synthase-CypD interaction, which in turn leads to mPTP opening.

231 d synthesized a new mitochondrially targeted CypD inhibitor, JW47, using a quinolinium cation tethere

232 We have reported before that CypD is downregulated and MPTP deactivated during differ

233 We conclude that CypD not only regulates the PTP, but also regulates the

234 nd loss-of-function experiments confirm that CypD has a limiting effect on cytochrome c release from

235 We found earlier that CypD is downregulated during osteogenesis of BMSCs leadi

236 Our data indicate that CypD indeed interacts with Bcl2 as confirmed with co-imm

237 We report that CypD interacts with the VDAC1/Grp75/IP3R1 complex in car

238 ependent differentiation model, we show that CypD is in fact transcriptionally repressed during this

239 Several reports have shown that CypD is overexpressed in various tumors, where it has an

240 The study shows that CypD binding with soluble alphaSyn prevents its aggregat

241 apoptotic stimuli as the WT, suggesting that CypD is not a central component of cell death in respons

242 The CypD-deficient cortical mitochondria are resistant to Ab

243 in D inhibitor, cyclosporine A, disrupts the CypD-Bcl2 interaction.

244 A dehydrogenase, which was acetylated in the CypD(-/-) hearts.

245 ellular NAD(+)/NADH ratio and normalized the CypD-deficient phenotype.

246 anscriptional activator of expression of the CypD gene, Ppif, during this process.

247 ation, as a transcriptional regulator of the CypD gene, Ppif.

248 drugs with crystallographic analysis of the CypD-ebselen crystal structure (PDB code: 8EJX).

249 drial permeabilization, independently of the CypD-regulated mPT, we coadministered the peroxynitrite

250 Thermodynamic profiles of the CypD/inhibitor interactions were determined by isotherma

251 Thus, the CypD-mediated mitochondrial permeability transition pore

252 ion of mitochondrial Ca(2+) overload via the CypD/VDAC1/Grp75/IP3R1 complex.

253 Therefore, CypD directs mitochondria-to-nuclei inflammatory gene ex

254 Thus, CypD inhibitors have the potential to slow the progressi

255 ntraperitoneal, 90 minutes prior to APAP) to CypD-deficient mice.

256 hat both NTD-DBD, NTD and NTD (1-70) bind to CypD at ~muM K(D).

257 orescence anisotropy detected DBD binding to CypD.

258 r's disease mouse models, which is linked to CypD-related membrane permeability transition pore forma

259 Genetic targeting of Hsp60 by siRNA triggers CypD-dependent mitochondrial permeability transition, ca

260 In vitro, CypD-deficient mitochondria showed an increased capacity

261 hat respond to metabolic demands and whether CypD regulates this dynamic.

262 re demonstrate a possible mechanism by which CypD achieves this and suggest that disaggregation could

263 whether there is one common pathway in which CypD and RIPK1 act in or whether separate RN pathways ex

264 Syn) is shown here to interact directly with CypD via its acidic proline-rich C-terminus region and b

265 nslocate into mitochondria and interact with CypD, triggering necrosis and cell growth arrest.

266 s, blockade of ATP synthase interaction with CypD provides a promising new target for therapeutic int

267 ral studies reported that p53 interacts with CypD through its DNA-binding domain (DBD).

268 Accordingly, mice with CypD-deficient platelets had fewer neutrophils and PNAs

269 to a similar degree as observed in mice with CypD-deficient platelets.

270 mbinant adenovirus encoding C203S-CypD or WT CypD into CypD(-/-) mice via tail vein.

271 Ca(2+)-induced swelling as compared with WT CypD-reconstituted mice.