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1、細(xì)胞凋亡的線粒體途徑蔣舜媛董霞程在全2002-12-17報(bào)告提綱細(xì)胞凋亡的特征細(xì)胞死亡損傷性死亡Necrosis程序化死亡、細(xì)胞凋亡ProgrammedCellDeathApoptosis細(xì)胞凋亡的特征形態(tài)學(xué)特征:染色質(zhì)的凝集,嗜堿性染色增強(qiáng),細(xì)胞核崩解此時(shí)線粒體保持形態(tài)正常.細(xì)胞體積縮小,一部分細(xì)胞質(zhì)和核碎片進(jìn)入由膜包被的程序死亡小體,他們從細(xì)胞表面出芽脫落,并被巨噬細(xì)胞.上皮細(xì)胞吞噬.生化特征:染色質(zhì)降解,核小體間連接DNA部位被降解,產(chǎn)生寡聚核小體DNA片段,即180-200DP整數(shù)倍的不同長(zhǎng)度的DNA片斷.Fig.1.Schematicsummaryofbiochemicalme
2、chanismsofapoptosis.MitochondriaandCommitmenttoCellDeath線粒體是真核細(xì)胞的重要細(xì)胞器，是動(dòng)物細(xì)胞生成ATP的主要地點(diǎn)。線粒體基質(zhì)的三羧酸循環(huán)酶系通過(guò)底物脫氫氧化生成NADH。NADH通過(guò)線粒體內(nèi)膜呼吸鏈氧化。與此同時(shí)，導(dǎo)致跨膜質(zhì)子移位形成跨膜質(zhì)子梯度和/或跨膜電位。線粒體內(nèi)膜上的ATP合成酶利用跨膜質(zhì)子梯度能量合成ATP。合成的ATP通過(guò)線粒體內(nèi)膜ADP/ATP載體與細(xì)胞質(zhì)中ADP交換進(jìn)入細(xì)胞質(zhì)，參與細(xì)胞的各種需能過(guò)程。MitochondriaandCommitmenttoCellDeaththeeffectorsofapoptos
3、isarerepresentedbyafamilyofintracellularcysteineproteasesknownascaspases.Inhibitingcaspases,however,doesnotalwaysinhibitcelldeathinducedbyproapoptoticstimuli.Althoughcaspaseinhibitorsblocksomeoralloftheapoptoticmorphologyinducedbygrowthfactorwithdrawal,etoposide,actinomycinD,ultraviolet(UV)radiat
4、ion,staurosporine,enforcedc-Mycexpression,orglucocorticoids,theydonotnecessarilymaintainreplicativeorclonogenicpotential;ultimately,thecellsdiedespiteinactivationofcaspasesbywayofaslower,nonapoptoticcelldeath(6-9).Incontrast,antiapoptoticproteinssuchasBcl-2,Bcl-xL,andoncogenicAblcanmaintainsurviv
5、alandclonogenicityinthefaceofthesetreatments.Conversely,someproapoptoticproteinssuchasBax,amammaliancelldeathproteinthattargetsmitochondrialmembranes,caninducemitochondrialdamageandcelldeathevenwhencaspasesareinactivated(10).Suchexperimentalobservationsarguethatacaspase-independentmechanismforcom
6、mitmenttodeathexists.Thismechanismislikelytoinvolvemitochondria,aswewillsee.MitochondrialPathwaysinphysiologicalcelldeaththereleaseofcaspaseactivators(suchascytochromec),changesinelectrontransport,lossofmitochondrialtransmembranepotential,alteredcellularoxidation-reduction,participationofpro-anda
7、ntiapoptoticBcl-2familyproteins.MitochondrialPathwaysinphysiologicalcelldeathIfmitochondriaarepivotalincontrollingcelllifeanddeath,thenhowdotheseorganelleskill?Atleastthreegeneralmechanismsareknown,andtheireffectsmaybe
