ライフサイエンスコーパス: mPTP

1 mPTP opening decreases the mitochondrial membrane potent

2 mPTP opening has been implicated as a final cell death p

3 mPTP-dependent alkalinization occurred in procoagulant p

4 mPTP-induced depolarisation under succinate subsequently

5 A mPTP inhibitor (TRO-19622) or a specific mitochondria RO

6 fects were negated by the addition of ATR--a mPTP opener--and mimicked by injection of NIM811--a mPTP

7 ener--and mimicked by injection of NIM811--a mPTP opening inhibitor.

8 or nonhepatic disorders related to abnormal mPTP opening.

9 mplex I-driven respiration was reduced after mPTP opening but sustained in the presence of complex II

10 nit of F-ATP synthase, helps protect against mPTP formation.

11 e whether mutation of C203S-CypD would alter mPTP in vivo, we injected a recombinant adenovirus encod

12 MKII inhibitory protein or cyclosporin A, an mPTP antagonist with clinical efficacy in ischaemia repe

13 Our findings reveal how an mPTP/UPR(mt) nexus may contribute to aging and age-relat

14 ethyl-4-isoleucine cyclosporine (NIM811), an mPTP inhibitor, were administered separately in selected

15 Accordingly, cyclophilin-D and mPTP were increased in heterozygous hearts, but genetic

16 a-AR stimulation that links CaMKII, Drp1 and mPTP to bridge cytosolic stress signal with mitochondria

17 Bcl-2 family proteins and mPTP-regulatory elements, such as adenine nucleotide tra

18 The activity of the cinnamic anilide mPTP inhibitors turned out to be additive with that of C

19 ochondrial ATP synthase does not function as mPTP and instead negatively regulates this pore.

20 n vivo evidence that, rather than serving as mPTP, the mitochondrial ATP synthase inhibits this pore.

21 s increased cyclophilin-D levels, as well as mPTP activation upon oxidative stress.

22 CypD(-/-) MEFs prior to H(2)O(2) attenuated mPTP opening.

23 ither iPLA2gamma or lipoxygenases attenuated mPTP opening in failing hearts.

24 marked enhancement of hepatocyte autophagy, mPTP opening, and death with ischemia/reperfusion injury

25 mal Ca(2+) uptake by the mitochondria before mPTP opening.

26 y preventing mitochondrial Ca(2+) influx, by mPTP inhibitor cyclosporine A, sanglifehrin, and in cycl

27 in a substrate-dependent manner, mediated by mPTP.

28 ets, integrin alphaIIbbeta3 epitope changes, mPTP formation, PS exposure, and platelet rounding were

29 ance consistent with this c-subunit channel (mPTP) in brain-derived submitochondrial vesicles (SMVs)

30 Clinically, mPTP opening and IRI complicate treatment of myocardial

31 mbrane function, but its role in controlling mPTP activity remains obscure.

32 eine 203 of cyclophilin D (CypD), a critical mPTP mediator, undergoes protein S-nitrosylation (SNO).

33 f coenzyme Q excess and relatively decreased mPTP open probability.

34 LA2gamma loss of function through decreasing mPTP opening, diminishing production of proinflammatory

35 which interacts with cyclophilin D to delay mPTP opening, were necessary to increase the Ca2+ uptake

36 e lacking all ANT isoforms, Ca(2+)-dependent mPTP opening persisted in cardiac mitochondria but was d

37 provides novel insights on the p53-dependent mPTP opening and drug discovery targeting NTD/CypD inter

38 therefore understanding conditions dictating mPTP opening is crucial for developing targeted therapie

39 e ATP synthase F1, providing a mechanism for mPTP opening.

40 nt, and dimer formation is not required, for mPTP activity.

41 Increasing the ROS threshold for mPTP induction enhances the resistance of cardiomyocytes

42 t Bax-driven fusion lowers the threshold for mPTP opening and necrosis.

43 Further, mPTP opening in cells lacking the mitochondrial ATP synt

44 To investigate the role of cysteine 203 in mPTP activation, we mutated cysteine 203 of CypD to a se

45 NO, suggesting a crucial role for Cys-203 in mPTP activation.

46 Consistent with the reported role of CypD in mPTP activation, CypD null (CypD(-/-)) MEFs exhibited si

47 creening molecules of interest implicated in mPTP regulation.

48 cyclophilin-D levels leading to reduction in mPTP activation.

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

50 tion and genetic silencing of SQOR increased mPTP open probability in vitro in adult murine cardiac m

51 btoxic levels both Ca(2+) and ROS can induce mPTP-mediated mitochondrial damage.

52 calcium stimuli become sufficient to induce mPTP opening in PINK1-deficient cells.

53 levels of ROS and Ca(2+) synergize to induce mPTP opening.

54 demonstrate sensitization of Ca(2+)-induced mPTP opening and desensitization by cyclophilin D inhibi

55 toyl-CoA markedly accelerated Ca(2+)-induced mPTP opening in liver mitochondria from wild-type mice.

56 mice demonstrated attenuated Ca(2+)-induced mPTP opening that could be rapidly restored by the addit

57 he functional consequences of Ca(2+)-induced mPTP opening were assessed by Ca(2+) retention capacity,

58 gene increased resistance to Ca(2+)-induced mPTP opening.

59 ive animals, rotenone administration induced mPTP formation, ROS generation, and NLRP3 inflammasome a

60 CoA-mediated augmentation of calcium-induced mPTP opening.

61 oA-mediated amplification of calcium-induced mPTP opening.

62 ablation protected against diabetes-induced mPTP opening, ATP synthesis deficits, oxidative stress,

63 Genetically induced mPTP opening blocks autophagy-dependent lifespan extensi

64 tant to Ca(2+)/t-butyl hydroperoxide-induced mPTP opening in comparison with wild-type littermates.

65 Drp1 activity blocks CaMKII- or ISO-induced mPTP opening and myocyte death in vitro and rescues hear

66 mPTP opening, attenuates isoflurane-induced mPTP opening, caspase 3 activation, and impairment of le

67 synergistic form of Ca(2+)- and ROS-induced mPTP opening persists in the absence of CypD (cyclophili

68 pected, Ca(2+) in the absence of ROS induces mPTP-dependent mitochondrial swelling.

69 These compounds can inhibit mPTP opening in response to several stimuli including ca

70 cued by treatment with sildenafil to inhibit mPTP opening or TUDCA to suppress ER stress.

71 of cyclosporine A being required to inhibit mPTP opening.

72 Inhibiting mPTP opening during the preconditioning phase with cyclo

73 kedly more potent than (S)-BEL in inhibiting mPTP opening in mitochondria from wild-type liver in com

74 While we have gained insight into mPTP biology over the last several decades, the lack of

75 in the absence of BSA, induced long-lasting mPTP opening, causing matrix depolarization.

76 CypD(-/-)) MEFs exhibited significantly less mPTP opening.

77 Our results link mPTP-mediated tumor necrosis to immune evasion and sugge

78 w insights into CypD-dependent mitochondrial mPTP and signaling on mitochondrial trafficking in axons

79 core component of the mPTP but can modulate mPTP through regulation of the basal mitochondrial Ca(2+

80 , indicating that cyclophilin D can modulate mPTP through substrates other than subunits in the assem

81 ated iPoC conferred protection by modulating mPTP.

82 oenergetics and lipidomic flux in modulating mPTP opening promoting the activation of necrotic and ne

83 anisms responsible for modulating myocardial mPTP opening remain unclear.

84 rome P450 epoxygenases opened the myocardial mPTP in human heart mitochondria.

85 grin beta3 cleavage and inactivation but not mPTP formation or PS exposure, indicating that integrin

86 additional tool to aid the search for novel mPTP modulators and to help understand its molecular nat

87 ly screen large compound libraries for novel mPTP modulators, a method was exploited to cryopreserve

88 esulting in protection against activation of mPTP and subsequent cell death responses.

89 ssary for redox stress-induced activation of mPTP.

90 Notably, blockade of mPTP by genetic deletion of CypD suppresses Abeta-mediat

91 Moreover, cyclosporine A, a blocker of mPTP opening, attenuates isoflurane-induced mPTP opening

92 ophilin D is the only confirmed component of mPTP.

93 state on the probability and consequences of mPTP opening.

94 -activated channels with the key features of mPTP.

95 ISO) persistently increases the frequency of mPTP openings followed by mitochondrial damage and cardi

96 The molecular identity of mPTP is unknown.

97 Altogether, the inhibition of mPTP and the increase in mitochondrial biogenesis may ac

98 Furthermore, inhibition of mPTP opening by cyclosporin A partially prevented Cyto C

99 both genetic and pharmacologic inhibition of mPTP opening restored the leukemic potential of primary

100 entified ER-000444793, a potent inhibitor of mPTP opening.

101 a2+ dynamics, we examined relative levels of mPTP components in synaptic versus nonsynaptic mitochond

102 f IPoC was associated with the modulation of mPTP opening.

103 rated that metformin inhibits the opening of mPTP and induces mitochondrial biogenesis.

104 inally, isoflurane may induce the opening of mPTP via increasing levels of reactive oxygen species.

105 ATR) and NIM811, which modify the opening of mPTP, were administered in selected groups.

106 confirm previous work showing persistence of mPTP in HAP1 cell lines lacking an assembled mitochondri

107 an unexpected role of HAX-1 in regulation of mPTP and cardiomyocyte survival.

108 gation identified ATP5PO, a key regulator of mPTP opening and a component of the ATP synthase complex

109 downstream products as potent regulators of mPTP opening, and demonstrate the integrated roles of mi

110 holipid scrambling with an assistant role of mPTP formation.

111 We review the role of mPTP opening in disease, discuss recent findings definin

112 ng an additional, CypD-independent effect on mPTP opening) and in primary human and mouse hepatocytes

113 residue (C203S) and determined its effect on mPTP opening.

114 small-molecule CypD inhibitors or vehicle on mPTP opening were assessed by measuring mitochondrial sw

115 ive oxygen species (ROS) levels, and an open mPTP.

116 ) may be molecularly related to pathological mPTP, but are likely to be normal physiological manifest

117 pore size is much smaller than for permanent mPTP, as neither Rhod-2 nor calcein (600 Da) were lost.

118 Furthermore, platelet mPTP formation resulted in a decreased ability to recrui

119 cate that, in strongly stimulated platelets, mPTP formation initiates the calpain-dependent cleavage

120 cular identity of the mitochondrial PT pore (mPTP) was previously unknown.

121 mitochondrial permeability transition pore (mPTP) and consequent membrane potential dissipation, lea

122 mitochondrial permeability transition pore (mPTP) and contribute to the production of oxidized fatty

123 mitochondrial permeability transition pore (mPTP) and the new phenomenon, superoxide flashes, and RO

124 mitochondrial permeability transition pore (mPTP) as a key end effector of ischemic/pharmacological

125 mitochondrial permeability transition pore (mPTP) based on the findings that cyclosporin A (CsA), a

126 mitochondrial permeability transition pore (mPTP) but the oligomeric state required for channel form

127 mitochondrial permeability transition pore (mPTP) by two research groups.

128 mitochondrial permeability transition pore (mPTP) drives maturation of mitochondrial structure and f

129 mitochondrial permeability transition pore (mPTP) formation, agonist-induced phosphatidylserine expo

130 Mitochondrial permeability transition pore (mPTP) formation, which is essential for the formation of

131 mitochondrial permeability transition pore (mPTP) in Abeta-impaired axonal mitochondrial trafficking

132 mitochondrial permeability transition pore (mPTP) inhibitors.

133 mitochondrial permeability transition pore (mPTP) is a channel in the inner mitochondrial membrane w

134 mitochondrial permeability transition pore (mPTP) is a pathological pore in the inner mitochondrial

135 mitochondrial permeability transition pore (mPTP) is implicated in cardiac ischemia-reperfusion (I/R

136 mitochondrial permeability transition pore (mPTP) is implicated in the pathogenesis of many disease

137 Mitochondrial permeability transition pore (mPTP) is involved in cardiac dysfunction during chronic

138 mitochondrial permeability transition pore (mPTP) may limit mitochondrial calcium load and mediate m

139 mitochondrial permeability transition pore (mPTP) opener, and N-methyl-4-isoleucine cyclosporine (NI

140 mitochondrial permeability transition pore (mPTP) opening and dissipation of the mitochondrial inner

141 mitochondrial permeability transition pore (mPTP) opening and failed antioxidant response.

142 mitochondrial permeability transition pore (mPTP) opening in brain mitochondria of diabetic mice, wh

143 mitochondrial permeability transition pore (mPTP) opening is a key pathophysiological event in cell

144 mitochondrial permeability transition pore (mPTP) opening plays a critical role in mediating cell de

145 mitochondrial permeability transition pore (mPTP) opening restores normal lifespan.

146 mitochondrial permeability transition pore (mPTP) opening, leading to a remarkable mitochondrial swe

147 mitochondrial permeability transition pore (mPTP) opening.

148 mitochondrial permeability transition pore (mPTP) openings damage mitochondria, but transient mPTP o

149 mitochondrial permeability transition pore (mPTP) or the inner membrane anion channel (IMAC), respec

150 Mitochondrial permeability transition pore (mPTP) plays crucial roles in cell death in a variety of

151 mitochondrial permeability transition pore (mPTP) restored immunosurveillance.

152 mitochondrial permeability transition pore (mPTP) such that physiological calcium stimuli become suf

153 mitochondrial permeability transition pore (mPTP) than nonsynaptic mitochondria.

154 mitochondrial permeability transition pore (mPTP) within the c-subunit of the ATP synthase.

155 mitochondrial permeability transition pore (mPTP), a high conductance channel that forms following r

156 mitochondrial permeability transition pore (mPTP), increase in levels of reactive oxygen species, re

157 mitochondrial permeability transition pore (mPTP), is a cellular catastrophe.

158 mitochondrial permeability transition pore (mPTP), precipitating mitochondrial dysfunction and cessa

159 mitochondrial permeability transition pore (mPTP), promoting cell death.

160 mitochondrial permeability transition pore (mPTP), resulting in disruption of mitochondria membrane

161 mitochondrial permeability transition pore (mPTP), which causes mitochondrial dysfunction and ultima

162 f mitochondria permeability transition pore (mPTP)-dependent cell death, which can be significantly r

163 mitochondrial permeability transition pore (mPTP).

164 mitochondrial permeability transition pore (mPTP).

165 mitochondrial permeability transition pore (mPTP).

166 mitochondrial permeability transition pore (mPTP).

167 mitochondrial permeability transition pore (mPTP).

168 mitochondrial permeability transition pore (mPTP).

169 mitochondrial permeability transition pore (mPTP).

170 mitochondrial permeability transition pores (mPTP) and trigger VDAC oligomerization.

171 long-lasting permeability transition pores (mPTP) causes respiratory uncoupling, mitochondrial injur

172 mitochondrial permeability transition pores (mPTP).

173 cilitated; mitochondrial membrane potential, mPTP, and ROS levels increased; and TUNEL positive nucle

174 ia through inhibition of fission potentiates mPTP opening in the absence of Bax/Bak or Mfn2, indicati

175 of these interactions to control and prevent mPTP induction when appropriate will enable us to decrea

176 mia reperfusion injury, equivalently prevent mPTP opening, DeltaPsim deterioration and diminish mitoc

177 nduced mitochondrial swelling, by preventing mPTP opening (half maximal inhibitory concentration valu

178 Here we show that CaMKII promotes mPTP opening and myocardial death by increasing MCU curr

179 cally channels AA into toxic HETEs promoting mPTP opening, which induces necrosis/apoptosis leading t

180 overload and oxidative stress that regulate mPTP opening have been well characterized, the compositi

181 yl-prolyl cis-trans isomerase that regulates mPTP opening in the inner mitochondrial membrane.

182 ATP5PO glutathionylation partially restored mPTP function and rescued AML cell viability following G

183 cannot support MOMP and apoptosis, restores mPTP opening and necrosis, implicating distinct mechanis

184 These mice showed similar mPTP dynamics and I/R sensitivity as the wild type, indi

185 We also studied mPTP opening after anoxia-reoxygenation in the presence

186 Mitoplast patch clamping studies showed that mPTP channel conductance was unaffected by loss of the m

187 3+/-3.1% with SfA; P<0.001), suggesting that mPTP opening during the preconditioning phase is require

188 The mPTP has been recently implicated in ROS generation via

189 Although the mPTP is known to be a voltage-gated channel, the identit

190 functions to enhance ROS production and the mPTP and NO trigger apoptosis; thus, the mPTP is a targe

191 osed to contribute to voltage sensing by the mPTP and may be a component of the voltage sensing appar

192 h, which can be significantly rescued by the mPTP inhibitor, Cyclosporin A (CsA).

193 While it has long been clear the mPTP is a druggable target, current agents are limited b

194 -subunit leak channel is a candidate for the mPTP.

195 ematode Caenorhabditis elegans initiates the mPTP and shortens lifespan specifically during adulthood

196 their strong dependence on IMAC and not the mPTP in this acute model of OS.

197 Using inhibitors of the mPTP (cyclosporine A or ADP) lipid peroxidation (ferrost

198 e we found decreased gating potential of the mPTP and increased expression and activity of sulfide qu

199 his series, able to attenuate opening of the mPTP and limit reperfusion injury in a rabbit model of a

200 We determined that dual inhibition of the mPTP and lipid peroxidation is significantly more protec

201 Putative components of the mPTP are expressed in mouse LGN, including the voltage-d

202 does not constitute a core component of the mPTP but can modulate mPTP through regulation of the bas

203 activated the Ca(2+)-induced opening of the mPTP in failing human myocardium, and the highly selecti

204 le inhibitors of CypD prevent opening of the mPTP in hepatocytes and the resulting effects in cell mo

205 Pharmacological or genetic inhibition of the mPTP inhibits the UPR(mt) and restores normal lifespan.

206 n well characterized, the composition of the mPTP is still actively investigated.

207 Manipulation of the mPTP markedly attenuated the early preapoptotic producti

208 gation) and the structural components of the mPTP pore, inducing pore opening.

209 Opening of the mPTP represents a major therapeutic target, as it can be

210 dysfunction and rupture independently of the mPTP through lipid peroxidation.

211 proaches to identify novel regulators of the mPTP with the hope of elucidating new therapeutic target

212 Pharmacologic and genetic closing of the mPTP yielded maturation of mitochondrial structure and f

213 ochondrial damage through the opening of the mPTP, although ROS mediates its damaging effects through

214 dings defining the putative structure of the mPTP, and explore strategies to identify novel, clinical

215 as an important mechanistic component of the mPTP, define its downstream products as potent regulator

216 cyclophilin D, an essential regulator of the mPTP, exhibited delayed progression to heart failure and

217 s considered to be the core component of the mPTP, is not affected by the loss of PPIase activity.

218 llular Ca(2+) pools in the regulation of the mPTP.

219 ce, suggesting substantial activation of the mPTP.

220 ndent mechanism for ROS sensitization of the mPTP.

221 s that modulates the gating potential of the mPTP.

222 at ER-000444793 acted as an inhibitor of the mPTP.

223 d a novel, CypD-independent inhibitor of the mPTP.

224 the total Ca(2+) levels required to open the mPTP.

225 Ca(2+) stores are sufficient to promote the mPTP opening.

226 strate in adult mouse brain neurons that the mPTP functions to enhance ROS production and the mPTP an

227 extends adult lifespan, suggesting that the mPTP normally promotes aging.

228 the mPTP and NO trigger apoptosis; thus, the mPTP is a target for neuroprotection in vivo.

229 target(s) that act at or in proximity to the mPTP.

230 euron apoptosis as are mice treated with the mPTP inhibitors TRO-19622 (cholest-4-en-3-one oxime) and

231 reticular Ca(2+) and extracellular Ca(2+) to mPTP opening in normoxic conditions or after anoxia-reox

232 indicate that the ANT family contributes to mPTP opening independently of CypD.

233 ase-CypD interaction, which in turn leads to mPTP opening.

234 y which chronic beta-AR stimulation leads to mPTP openings is elusive.

235 electron transfer sensitised mitochondria to mPTP opening.

236 omplex III did not sensitise mitochondria to mPTP opening.

237 bsence of Bax/Bak renders cells resistant to mPTP opening and necrosis, effects confirmed in isolated

238 3S-CypD reconstituted MEFs were resistant to mPTP opening in the presence or absence of GSNO, suggest

239 mediated by distinct pathways subsequent to mPTP formation.

240 However, low conductance and transient mPTP openings (tPTP) might limit mitochondrial Ca(2+) lo

241 could be explained by asynchronous transient mPTP openings allowing individual mitochondria to depola

242 openings damage mitochondria, but transient mPTP openings protect against chronic cardiac stress.

243 ced CsA-sensitive, low-conductance transient mPTP opening (represented by a 28+/-3% reduction in mito

244 mitochondrial uncoupling requires transient mPTP opening and ROS.

245 We hypothesize that transient mPTP opening and ROS mediate the protection associated w

246 Our results show that transient mPTP openings allow cardiac mitochondria to defend thems

247 We found that transient mPTP openings also stimulated reactive oxygen species pr

248 akage from internal stores could not trigger mPTP opening by itself but significantly decreased the C

249 asmic reticulum is not sufficient to trigger mPTP opening and corresponds to ~50% of the total Ca(2+)

250 CypD is hypothesized to trigger mPTP opening through isomerization of ANTs at proline-62

251 2+), we determined that ROS fails to trigger mPTP opening.

252 I/R, elevated mitochondrial Ca(2+) triggers mPTP opening, leading to necrotic cell death.

253 al free [Ca(2+)] increase to >10 muM, unless mPTP openings were inhibited.

254 ategies to identify novel, clinically useful mPTP inhibitors, highlighting key considerations in the

255 50 bp fragments that exited mitochondria via mPTP- and VDAC-dependent channels to initiate cytosolic

256 0-fold slower than matrix Ca(2+) release via mPTP, only a tiny fraction of mitochondria (<1%) are dep

257 of CyPD and VDAC oligomers, consistent with mPTP formation.

258 Treatment with mPTP inhibitors rescue mitochondrial function and thermo