细胞凋亡的线粒体途径.pptVIP

PTPore的性质通过一些实验室的研究，以下诸点值得指出：线粒体内膜通透性转变既是细胞凋亡的必须条件，也是它的充足条件。PT孔道打开后导致线粒体许多功能的致命性变化从而启动了死亡途径。PT孔道作为许多生理效应的感受器（二价阳离子、ATP、ADP、NAD、ΔΨm、pH、巯基与多肽)，整合了电生理、氧化还原与细胞代谢状态的信息。PT孔道的组成成分ADP-ATP载体是能量代谢的重要分子，由于ADP-ATP载体是由一个基因家族的几个成员所编码，它的表达有严格的组织专一性。因此，PT孔道在不同细胞中的调节可能稍有不同。PT孔道的作用有自放大的效应。PT诱导ΔΨm耗散，而反过来mClCCP使ΔΨm去极化会导致PT。一些PT的结果例如ΔΨm耗散，活性氧的生成本身也会导致PT。这就说明PT会有正反馈，从而在细胞凋亡中有自摧毁的作用。反过来，如果能防止ΔΨm的耗散，就能避免氧化还原不平衡、磷酯酰丝氨酸的暴露与蛋白酶和核酸酶的激活。Figure2.Schematicsummaryofbiochemicalmechanismsofapoptosis.Cyto-c=cytochromeC;Mito=mitochondrium.1011Figure1.Modelforcaspaseactivationbymitochondria.MultiplestimulisuchasBax,oxidants,Ca2+overload,activecaspases,andperhapsceramidecantriggermitochondriatoreleasecaspase-activatingproteins,amongwhicharecytoc(solidcircles)andpossiblyotherproteinssuchasAIFandintramitochondrialcaspases(opencircles).Twogeneralmechanismsforreleaseofcaspase-activatingproteinsfrommitochondriahavebeenproposed:oneinvolvesosmoticdisequilibriumleadingtoanexpansionofthematrixspace,organellarswelling,andsubsequentruptureoftheoutermembrane(left);theotherenvisionsopeningofchannelsintheoutermembrane(withoutconcomitantorganellarswelling),thusreleasingcytocfromtheintermembranespaceofmitochondriaintothecytosol.CytocactivatescaspasesbybindingtoApaf-1,inducingittoassociatewithprocaspase-9,therebytriggeringcaspase-9activationandinitiatingtheproteolyticcascadethatculminatesinapoptosis.Cellsinwhichmitochondriahaverupturedareatriskfordeaththroughaslowernonapoptoticmechanismresemblingnecrosisbecauseoflossoftheelectrochemicalgradientacrosstheinnermembrane(m),productionofROS,anddecliningATPproduction.Figure2.Themitochondrialpermeabilitytransition.Aspeculativemodelshowingsomeofthecomponentsofthepermeabilitytransitionpore.Therolesofporinandthebenzodiazepinereceptorremaincircumst