活性氧_线粒体通透性转换与细胞凋亡_马淇

:ACTABIOPHYSICASINICAVol.28No.7Jul.2012:523-536523-536、1,2,1,11.1001012.191042012-06-202012-07-02+1(215)[e-mail](010)[e-mail]，，（mitochondrialpermeabilitytransition，MPT）（mitochondrialpermeabilitytransitionpore，MPTP）。，c，，。。，，，。、，，。；；；Q73DOI10.3724/SP.J.1260.2012.20103。。。。(reactiveoxygenspeciesROS)。ROS(superoxideanionO2·－)、(hydrogenperoxideH2O2)、(hydroxylradical·OH)、523ACTABIOPHYSICASINICA｜Vol.28No.7｜Jul.2012/MiniReview20122873ETCO2·－ETCROSFig.3ProductionofprimaryROSinmitochondriaComplexandarethemainresourceofintracellularO2·－generationIntermembranespaceMatrixH+H+H+H+eeeeO2O2O2·－O2·－Innermembrane1%～2%ETC[5]O2·－。O2·－ROS(primary)。0.2%O2·－[6]。5O2·－(3)。(NADHNADH-Q)20%O2·－(Q-c)80%O2·－[7,8]。2ETCETCFig.2ComponentsofETCintheinnermitochondrialmembraneArrowsshowelectrontransportationduringtheprogressofrespirationSuccinateNADHFMNFADFeSFeSCoQCytb562Cytc1Cytb556FeSCytcCytaCyta3O21O2H2OROSFig.1ThreeisoformsofROSgeneratedduringthereductionofO2toH2OO2O2·－H2O2·OHH2O(singletoxygen,lO2)。O2·－、H2O2、·OHO2H2O3(1)[1]。ROSNAD(P)H(NADPHoxidase)、(peroxisome)、P450(cytochromeP450)、(xanthineoxidase)、(cyclooxygenase)(lipooxygenase)[2,3]。(electrontransportchainETC)(respiratorychain)ROS。ROS95%[4](2)。e524｜ACTABIOPHYSICASINICA、/MiniReview1ROSTable1DistinguishingfunctionsofdifferentisoformsofROSROSO2·－·OHlO2O2·－H2O2·OH50[8][9]ROS、。ROS。ROS[10]、、、、、[2,11,12]。ROS70ROS(cGMP)[10]ROS。ROS(redoxsignaling)。。ROSAP-1NF-kB、Src、JNK、MAPK、[2]。H2O2ROS、。ROS(oxidativestress)、DNA(oxidativedamage)、、、[2,3,13～15]。H2O2ROSROS。ROSDNADNA[3]、。ROS。ROS、[16](1)。ROS。ROS、。ROS。ROS。ROS。。(PorinVDAC)5kDa(4)。、。525ACTABIOPHYSICASINICA｜Vol.28No.7｜Jul.2012/MiniReview2012287、、ATP(ΔΨm)。(mitochondrialpermeabilitytransitionMPT)。60。Ca2+、(swelling)[17,18]。Ca2+[19]。(mitochondrialpermeabilitytransitionporeMPTP)MPT[20～23]。MPTP1.5kDa[24,25]。MPTP(transient)(reversible)MPT(transientMPTtMPT)。tMPT[26]。MPTP(consistent)(irreversible)MPT(irreversibleMPTiMPT)ATP[24,27]。Na+、K+、Ca2+。。。MPTP(selectivemitochondrialclearance)(qualitycontrol)(mitophagy)。MPT[28]。MPTP。MPTP。MPTPMPTP。MPTP、、。MPTP(voltage-dependentanionchannelVDAC)、(adeninenucleotidetranslocaseANT)、cyclophilinD(CypD)。MPTP(hexokinaseHK)、(creatinekinaseCK)(4)。CypD。CypD18kDappif[29]。CypDMPTCypDMPTP[30～32]。CypD。CypD526｜ACTABIOPHYSICASINICA、/MiniReview4MPTPFig.4ThemolecularcompositionofMPTPCytosolOutermembraneIntermembranespaceInnermembraneMatrixH2O,H+,K+,Na+,molecules＜5kDapH~7.4pH~7.4pH~8.0CKHKCypDANTANTVDACVDACMPT。CypDCypDMPTCypDMPT[33～36]。CypDMPTPMPT。CypDMPTP。ANTCypDMPTP。ANTATPADP。ANT4ANT1ANT2ANT3ANT4[37～39]。ANTMPTANTMPTP[40～43]。ANTCypDMPTPANT1ANT2MPT[44～46]。ANT1、ANT2MPT[47]。ANTMPTPMPT。VDAC。VDACVDAC[48～51]。VDAC5kDaVDAC1.5kDa[52,53]。VDAC4VDAC1、VDAC2VDAC365%～70%VDAC4[32,54]。VDACNα16β527ACTABIOPHYSICASINICA｜Vol.28No.7｜Jul.2012/MiniReview20122875MPTPFig.5RegulationofthecomplexofMPTPCa2+,ROS,OH－,PiCTrifluoperazineGSH,NAD(P)HMg2+,Sr2+,Mn2+CytosolIntermembranespaceMatrixCyclosporinABongkrekicAADP/ATPInnermembraneOutermembraneCypDANTANTCKVDACVDAC[55～57]。VDAC[49,58]。VDACMPTPVDACMPTPVDACMPT[59～61]。VDACMPTPMPT[62]。VDAC1VDAC1、VDAC3MPT。VDACMPTP。VDAC2VDACMPT[63～66]。VDACMPTPMPT。MPTPMPTP。(phosphatecarrierPiC)、-(aspartate-glutamatecarrierAGC)、-(ornithine-citrullinecarrierOCC)、ETCI[67,68]。MPTPMPT[28,39,69～74]。MPTP。MPTPMPTPMPTP(5)。MPTP。Ca2+MPTCa2+MPTP。NAD(P)H、ADP/ATP、、ETC、、528｜ACTABIOPHYSICASINICA、/MiniReviewROS、MPTP[75]。MPTPCypDANT。CypDCsA(cyclosporinA)CypDMPT[76]。calcineurinCsA[77]。ANTBA(bongkrekicacid)MPTP[40]。TrifluoperazineMg2+、Sr2+、Mn2+MPTP[78～80]。ADP/ATPMPTP[22,81,82]。(apoptosis)(programmedcelldeath)、、、、。、、。、、[83～86]。、、。70[87]。。(extrinsic)()(intrinsic)[88]。。。(initiation)、(commitment)(execution)[89]。、。c(CytochromcCytc)。CytcCaspaseDNA。Cytc、(6。CytcBcl-2。Bcl-2。(anti-apoptoticsubset)Bcl-2、Bcl-xL、Bcl-w、Bcl2A1、Bcl-BMcl-1Bcl-2(BHdomain)BH1、BH2、BH3BH4。(pro-apoptoticsubset)Bax、BakBokBH1、BH2BH3。BH3-only(BH3-onlysubset)Bid、Bim、Bik、Bad、Noxa、Puma、BMFHRKBH3。BH3Bcl-2529ACTABIOPHYSICASINICA｜Vol.28No.7｜Jul.2012/MiniReview20122876c(A)Bax、BakMPTCytc(B)iMPTCytcFig.6SignalingpathwaysmediatingCytcrelease(A)Mega-poreformedwithBax/BakreleasesCytc;(B)Irreversiblemitochondrialpermeabilitytransition(iMPT)triggersmitochondrialswellingandCytcreleaseApoptoticsignalsH2OCa2+,ROSCytcBaxBakBcl-2MPTPApoptosisCaspaseactivationROS↑△ψ↓Swelling(A)(B)。Bcl-2。BaxBcl-2,Bak、MPTPCytc。BaxBakBakBaxCytc。Bcl-2Bax。BH3-onlyBax/BakBH3-onlyBcl-2。(Bcl-2)(Bax、Bak)。Bcl-2MPTPCytc。ROSMPTP。MPTP(swelling)(6)。(Cytc)。ROSCa2+MPTP。Bcl-2CytcMPTPCytc。BaxMPTPBaxMPTP。Bcl-2(Bcl-2、Bcl-xL)MPTP。、MPT、(mitochondrialapoptosis)。530｜ACTABIOPHYSICASINICA、/MiniReview7ROS、MPTFig.7ROS,MPTandmitochondrialapoptosisROSMPTApoptosis4)MPTmediatesCytcrelease3)Bcl-2familyproteinsregulateMPT1)ROSactivatesMPTPopening2)MPTPopeningreleasesROS5)ApoptosisresultsinROSburst6)Oxidativestressinducesapoptosis7。71)ROSMPTPMPTP[75]。MPTP(tMPT)ROS。()MPTP[90～92]。2)(commitment)MPTPATPROS[93]。3)Bcl-2MPTP。BaxMPTP。Bcl-2MPTP[94]。Bcl-2MPTP[92]