细胞器与疾病(1)PPT课件.ppt

1,细胞器与疾病（分子医学）,2,Amammaliancell,3,Nucleus,Thenucleusisamembraneboundstructurethatcontainsthecellshereditaryinformationandcontrolsthecellsgrowthandreproduction.Itiscommonlythemostprominentorganelleinthecell,NuclearMembranes,Thenuclearcontentislocatedinthenuclearlumenandissurroundedbyadoublemembraneornuclearenvelope,composedofinnermembraneandoutermembrane.TheoutermembraneiscontiguouswiththeERThenuclearmembranecontainsnuclearpores,whichprovideselectiveaccessintoandoutofthenuclearlumenTheinnermembranehasaproteinliningcalledthenuclearlamina,whichbindstochromatinandothernuclearcomponents.,5,TheNuclearPoreComplexesformacontinuousaqueouschannelbetweencytoplasmbasicsubunitrepeated16times.“Centralgranulenowcalledtransporterfunctionstomovemoleculesthroughpore.ThereisaringofproteinsthatanchorsporetoN.E.andthebasketoffiberswithunknownfunctionnoobviousmotorproteinswerefound,6,TheNucleolus,TheregionofthenucleuswhereportionsofchromosomesthatcontaingenescodingforribosomalRNAaretranscribedandribosomalsubunitsareassembled,StretchofDNAwithrRNAgenesnucleolarorganizingregion=(NOR)RibosomalproteinsaresynthesizedincytoplasmandtransportedintothenucleusTheseproteinsselfassociatewithappropriaterRNAduringrRNAsynthesisformingimmatureribosomalsubunitsRibosomesfinishselfassemblyincytoplasm,7,EndoplasmicReticulum,8,KEDLR-GFP,激光共聚焦显微镜下的ER,9,TheEndoplasminReticulum(ER)isanextensive,extra-nuclearmembranesystemwiththefollowingfunctions:,ERisahomeforvariousenzymesinvolvedinproteinfolding,drugdetoxification,membranelipidbiosynthesis,cholesterolandfattyacidmetabolismERisanentrypointforproteinsorting.Targetingoftheseproteinsismediatedbysignalsequence.ThemembraneproteinsareinsertedintotheERmembraneintheirproperorientation.SecretedproteinsaretranslocatedintoERlumenandthentransportedtothedestinationplace,10,RoughandSmoothER,TworegionsoftheERdifferinbothstructureandfunction.RoughERhasribosomesattachedtothecytoplasmicsideofthemembrane.SmoothERlacksattachedribosomes.Typically,thesmoothERisatubulenetworkandtheroughERisaseriesofflattenedsacs.,:8001/esgbio/cb/org/er.gif,ThesmoothERhasawiderangeoffunctionsincludingcarbohydrateandlipidsynthesis.ItservesasatransitionalareaforvesiclesthattransportERproductstovariousdestinations.InlivercellsthesmoothERproducesenzymesthathelptodetoxifycertaincompounds.InmusclesthesmoothERassistsinthecontractionofmusclecellsandinbraincellsitsynthesizesmaleandfemalehormones.,11,TheroughERmanufacturesmembranesandsecretoryproteins,TheroughandsmoothERareUsuallyinterconnectedandtheproteinsandmembranesmadebytheroughERmoveintothesmoothERtobetransferredtootherlocations.,Thecytoplasmhasareducingenvironment,whileERlumenisoxidizing.Thisdifferenceisgeneratedbyunequaldistributionoftrypeptideglutathioneandisessentialforformationofdisulfidebondsinproteinsandforproperfolding,12,ERfunction-relateddiseases,内质网应激与心血管疾病内质网与细胞凋亡内质网与PrPandMadCow,13,Mitochondria,14,Mitochondria(singular:mitochondrion)arethesitesofaerobicrespiration,andgenerallyarethemajorenergyproductioncenterineukaryotes,Thenumberofmitochondriarangefromonetothousandspercells.TheyareoftenpositionedincellsnearesttositesofenergyutilizationOneoftherichestsourcesofmitochondriaisahummingbirdflightmuscle,15,Mitochondriaareadoublemembraneorganelleinwhichtheinnermembraneisin-foldedtoform“cristae”.,Theoutermembraneisafairlysimplephospholipidbilayer,containingporins,proteinsthatrenderitpermeabletomoleculesofabout10kilodaltonsorless.Ions,nutrientmolecules,ATP,ADP,etc.easilypassthroughtheoutermembraneandentertheintermembranespaceTheinnermembraneismorecomplexandcontainsrespiratorychainsandtransporters,Thematrixlieswithintheinnermembrane.Theaccesstothiscompartmentoftenrequiresspecifictransporters,16,Fourpossiblelocalizationformitochondrialenzymes,17,TheGolgiComplex,18,Locatednearcellnucleus,consistsofflattened,membrane-boundedsacs(cisternae)formingastack,Eachstackhas:cis-faceisanentryface-adjacenttoERtoacceptincomingvesicles,trans-faceisanexitfacepointstowardsplasmamembrane,producesvesiclesforforwardflow,19,ThefunctionoftheGolgiistotransportandprocesssecretedandmembraneproteinsfromERtothecellsurface,Cisremovalofmannose,phosphorylationMedialremovalofmannose,additionofN-acetylglucosamineTransRemovalofgalactose,additionofsialicacidTGNadditionofsialicacid,Sorting,Cisternaesegregatedintoconvex(cis),medial(middle),andconcave(trans)compartments.,ER,cys,medial,trans,TGN,20,VesicularTransport,21,Golgistructure/function/-relateddiseases,GolgiandMitosisGolgiandApoptosisGolgiandLiverCancer,22,HNEinducesGolgiFragments,Control,30min,1h,2h,4h,23,TheEndocyticPathway,EndosomesandLysosomes,24,25,Lysosomes,26,1、初级溶酶体直径约0.20.5um膜厚7.5nm，内含物均一，无明显颗粒，是高尔基体分泌形成的（如右图）。含有多种水解酶，但没有活性，只有当溶酶体破裂，或其它物质进入，才有酶活性。其水解酶包括蛋白酶，核酸酶、脂酶、磷酸酶、硫酸酯酶、磷脂酶类，已知60余种，这些酶均属于酸性水解酶，反应的最适PH值为5左右，溶酶体膜虽然与质膜厚度相近，但成分不同，,27,2、次级溶酶体这些都是消化泡，正在进行或完成消化作用的溶酶体，内含水解酶和相应的底物，可分为自噬溶酶体（autophagolysosome）和异噬溶酶体（phagolysosome），前者消化的物质来自细胞本身的各种组分,后者消化的物质来自外源。,28,3、残体又称后溶酶体（post-lysosome）已失去酶活性，仅留未消化的残渣故名，残体可通过外排作用排出细胞，也可能留在细胞内逐年增多，如肝细胞中的脂褐质（如右图）。,29,LysosomesLysosomesareactiveinrecyclingthecellsorganicmaterialandintheintracellulardigestionofmacromolecules.Lysosomescontainvarioushydrolyticenzymesthatarecapableofdigestingnucleicacids,polysaccharides,fatsandproteins.Theinsideofalysosomeisacidic.Inhumans,avarietyofinheritedconditionscanaffectlysosomes.Thesedefectsarecalledstoragediseases.Peoplewiththesedisordersaremissingoneormoreofthelysosomalhydrolyticenzymes.,30,动物细胞溶酶体系统示意图,31,Lysosome-relateddiseases,溶酶体酶缺失或溶酶体酶的代谢环节故障，影响细胞代谢，引起疾病。如台-萨氏（Tay-Sachs）等各种储积症（隐性的遗传病）。某些病原体（麻疯杆菌、利什曼原虫或病毒）被细胞摄入，进入吞噬泡但并未被杀死而繁殖（抑制吞噬泡的酸化或利用胞内体中的酸性环境）。类风湿性关节炎溶酶体膜很易脆裂，其释放的酶导致关节组织损伤和发炎。矽肺二氧化硅尘粒（矽尘）吸入肺泡后被巨噬细内吞噬，含有矽尘的吞噬小体与溶酶体合并成为次级溶酶体。二氧化硅的羟基与溶酶体膜的磷脂或蛋白形成氢键，导致吞噬细胞溶酶体崩解，细胞本身也被破坏，矽尘释出，后又被其他巨噬细内吞噬，如此反复进行。受损或已破坏的巨噬细胞释放“致纤维化因子”，并激活成纤维细胞，导致胶原纤维沉积，肺组织纤维化。,32,TheCytoskeleton,33,Cytoskeletonisanetworkofproteinfilamentsinthecytoplasm,Mainfunctions:Supportslargevolumeofthecytoplasm.Participatesinlarge-scalemovementsassociatedwiththechangesincellshapeandcellmotility.Providesmachineryfororganelletransport,chromasomesegregationduringmitosis,andcelldivision.,34,Actinfilaments,Microtubules,Intermediatefilaments,Majorcomponentsofcytoskeleton,35,Thecytoskeletalfilaments,CommonFeatures:LinearpolymersofproteinsubunitsActin(8nmindiameter)IntermediateFilaments(10nmindiameter)Microtubules(24nmindiameter)Filamentsaredynamic,i.e.theycanassembleanddisassembleHighlyconserved,IntermediateFilaments,Intermediatefilamentsenablecellstowithstandmechanicalstresswhencellsarestretched.Theycanspantheentirecytoplasmandareanchoredtotheplasmamembrane.,38,TheMicrotubuleCytoskeleton,AlsopenetratestheentirevolumeofthecellWhereasactinfibersareconcentratedattheperiphery,mostmicrotubulesradiatefromacentrallocationinthecellMainfunctions:intracellulartransportandmitosis,Microtubulesprovideanorganizationalstructureinaninterphasecellandseparatechromosomesinadividingcell,/external/Frank.Gibbons/spindle.html,Microtubules,MicrotubulesProvideTracksforTransport,Microtubulesarelonghollowcylindersmadeoftubulin,Protofilamentsarelinearchainsoftubulindimers,aparallelbundleof13protofilamentsformsamicrotubuleTherearethreekindsoftubulins,eachwithmanysubtypes:a-tubulinandb-tubulinforma/btubulindimersandrepresentthebasicbuildingblockofmicrotubulesg-tubulinisinvolvedinmorespecializedprocesses,suchasnucleationMicrotubuleshaveaGTP“cap”stabilizingtheends.,MotorProteins,MotorproteinsbindtomicrotubulesandmovebycyclesofconformationalchangesusingenergyfromATP.Oneendoftheproteincanbindtospecificcellularcomponents.,43,ActinisthemostcommonproteininthecytoplasmActinfilamentsareconcentratedbeneaththeplasmamembraneandgivethecellmechanicalstrengthAssemblyofactinfilamentscandeterminecellshapeandcausecellmovementAssociationofactinfilamentswithmyosincanformcontractilestructures,Actinfilaments=microfilaments,44,核蛋白体,在粗面内质网表面的称固着核蛋白体，在细胞质内分散存在的称游离核蛋白体。数个或致十个核蛋白体聚集在一起称多聚核蛋白体，系由信息核糖核酸(mRNA)将核蛋白体串连在一起形成。,45,核蛋白体在一定浓度的镁离子溶液内，可分成一大一小两个亚单位。分别称为大亚基与小亚基，可用超速离心法将两者分开。两个亚基合在一起时，由于一大一小，形成葫芦状。核蛋白体与蛋白质合成有密切关系，是氨基酸根据mBNA中的遗传密码顺序形成多肽的场所。合成内用蛋白质多的细胞，游离的核蛋白体丰富，如幼稚细胞或胚胎细胞。合成外用蛋白质多的细胞，则粗面内质网丰富，例如肝细胞、胰腺泡细胞及浆细胞等。,46,中心粒(centrio1es),中心粒与细胞分裂有关，在间期，中心粒常在细胞核一侧。中心粒呈短简状，成双存在，彼此垂直分布，又称双体(diplosome)。每个中心粒由9组三联体构成，彼此成45，使9组三联体排列成风车状。每个三联体由3根微管组成。在核分裂时，双体复制，并移向细胞的两极。以后各端中心粒的纺锤丝与染色体相连，并将染色体引向两极，形成二个核。,47,线粒体遗传病,48,1894年，首次发现,49,1897年，正式命名为mitochondrion(线粒体),50,1963年，Nass在鸡胚中发现线粒体中存在DNA,Schatz分离到完整的线粒体DNA,1981年，测定人mtDNA的DNA序列,1987年，Wallac提出mtDNA突变可引起疾病,1988年，首次报道mtDNA突变,51,mtDNA的结构和遗传特征,mtDNA的结构特点,线粒体是细胞质中独立的细胞器，也是动物细胞核外唯一的含有DNA(mitochondrialDNA，mtDNA)的细胞器。,1981年，剑桥大学的Anderson小组测定了人mtDNA的完整DNA序列，称为“剑桥序列”。,由于缺乏组蛋白的保护，线粒体亦缺乏DNA损伤修复系统，mtDNA的突变率较高。,52,人mtDNA是一个长为16,569bp的双链闭合环状分子，外环含G较多，称重链(H链)，内环含C较多，称轻链(L链)。,mtDNA的结构和遗传特征,53,mtDNA结构紧凑，没有内含子，唯一的非编码区是D环区，长约1,000bp左右。,D环区包括mtDNA重链复制起始点，重轻链转录的启动子。,54,线粒体的H链是12种多肽链、12SrRNA、16SrRNA和14种tRNA的转录模板，L链是1种多肽链和8种tRNA转录的模板。,人类的mtDNA编码13条多肽链、22种tRNA和2种rRNA。13种蛋白质均是呼吸链酶复合物的亚单位。,55,由于缺乏组蛋白的保护，线粒体亦缺乏DNA损伤修复系统，mtDNA的突变率较高。,一、mtDNA的结构特征,线粒体是细胞质中独立的细胞器，也是动物细胞核外唯一的含有DNA的细胞器。,1981年，剑桥大学的Anderson小组测定了人mtDNA的完整DNA序列，称为“剑桥序列”。,第一节mtDNA的结构和遗传特征,56,1.mtDNA具有半自主性,mtDNA的遗传学特性,57,mtDNA的UGA编码色氨酸，而非终止信号。其tRNA的通用性较强，22个tRNA可识别48个密码子。,3.mtDNA为母系遗传,2.mtDNA的遗传密码与通用密码不同,1.mtDNA具有半自主性,mtDNA的遗传学特征,58,mtDNA的母系遗传,59,1、母亲将她的mtDNA传递给儿子和女儿，但只有女儿能将其mtDNA传递给下一代；2、人的细胞里通常有上千个mtDNA拷贝，在突变体和正常mtDNA共存的