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1、细胞器与疾病 （分子医学）,A mammalian cell,Nucleus,The nucleus is a membrane bound structure that contains the cells hereditary information and controls the cells growth and reproduction. It is commonly the most prominent organelle in the cell,Nuclear Membranes,The nuclear content is located in the nuclear lume
2、n and is surrounded by a double membrane or nuclear envelope, composed of inner membrane and outer membrane. The outer membrane is contiguous with the ER The nuclear membrane contains nuclear pores, which provide selective access into and out of the nuclear lumen The inner membrane has a protein lin
3、ing called the nuclear lamina, which binds to chromatin and other nuclear components.,The Nuclear Pore Complexes form a continuous aqueous channel between cytoplasm & nucleoplasm,- nuclear pore complex is large about 120 million Daltons -30 different proteins found in pore; basic subunit repeated 16
4、 times. “Central granule“ now called “transporter“ functions to move molecules through pore. There is a ring of proteins that anchors pore to N.E. and the “basket“ of fibers with unknown function no obvious motor proteins were found,The Nucleolus,The region of the nucleus where portions of chromosom
5、es that contain genes coding for ribosomal RNA are transcribed and ribosomal subunits are assembled,http:/ of DNA with rRNA genes nucleolar organizing region = (NOR) Ribosomal proteins are synthesized in cytoplasm and transported into the nucleus These proteins self associate with appropriate rRNA d
6、uring rRNA synthesis forming immature ribosomal subunits Ribosomes finish self assembly in cytoplasm,Endoplasmic Reticulum,KEDLR-GFP,激光共聚焦显微镜下的ER,The Endoplasmin Reticulum (ER) is an extensive, extra-nuclear membrane system with the following functions:,ER is a home for various enzymes involved in p
7、rotein folding , drug detoxification, membrane lipid biosynthesis, cholesterol and fatty acid metabolism ER is an entry point for protein sorting. Targeting of these proteins is mediated by signal sequence. The membrane proteins are inserted into the ER membrane in their proper orientation. Secreted
8、 proteins are translocated into ER lumen and then transported to the destination place,Rough and Smooth ER,Two regions of the ER differ in both structure and function. Rough ER has ribosomes attached to the cytoplasmic side of the membrane. Smooth ER lacks attached ribosomes. Typically, the smooth E
9、R is a tubule network and the rough ER is a series of flattened sacs.,http:/esg-www.mit.edu:8001/esgbio/cb/org/er.gif,The smooth ER has a wide range of functions including carbohydrate and lipid synthesis. It serves as a transitional area for vesicles that transport ER products to various destinatio
10、ns. In liver cells the smooth ER produces enzymes that help to detoxify certain compounds. In muscles the smooth ER assists in the contraction of muscle cells and in brain cells it synthesizes male and female hormones.,The rough ER manufactures membranes and secretory proteins,The rough and smooth E
11、R are Usually interconnected and the proteins and membranes made by the rough ER move into the smooth ER to be transferred to other locations.,The cytoplasm has a reducing environment, while ER lumen is oxidizing . This difference is generated by unequal distribution of trypeptide glutathione and is
12、 essential for formation of disulfide bonds in proteins and for proper folding,ER function-related diseases,内质网应激与心血管疾病 内质网与细胞凋亡 内质网与PrP and Mad Cow,Mitochondria,Mitochondria (singular: mitochondrion) are the sites of aerobic respiration, and generally are the major energy production center in eukar
13、yotes,The number of mitochondria range from one to thousands per cells. They are often positioned in cells nearest to sites of energy utilization One of the richest sources of mitochondria is a hummingbird flight muscle,Mitochondria are a double membrane organelle in which the inner membrane is in-f
14、olded to form “cristae”.,The outer membrane is a fairly simple phospholipid bilayer, containing porins, proteins that render it permeable to molecules of about 10 kilodaltons or less. Ions, nutrient molecules, ATP, ADP, etc. easily pass through the outer membrane and enter the intermembrane space Th
15、e inner membrane is more complex and contains respiratory chains and transporters,The matrix lies within the inner membrane. The access to this compartment often requires specific transporters,Four possible localization for mitochondrial enzymes,The Golgi Complex,Located near cell nucleus, consists
16、of flattened, membrane-bounded sacs (cisternae) forming a stack,Each stack has: cis-face is an entry face - adjacent to ER to accept incoming vesicles,trans-face is an exit face points towards plasma membrane, produces vesicles for forward flow,The function of the Golgi is to transport and process s
17、ecreted and membrane proteins from ER to the cell surface,Cis removal of mannose, phosphorylation Medial removal of mannose, addition of N-acetylglucosamine Trans Removal of galactose, addition of sialic acid TGN addition of sialic acid, Sorting,Cisternae segregated into convex (“cis“), medial (midd
18、le), and concave (“trans“) compartments.,ER,cys,medial,trans,TGN,Vesicular Transport,Golgi structure/function/-related diseases,Golgi and Mitosis Golgi and Apoptosis Golgi and Liver Cancer,HNE induces Golgi Fragments,Control,30 min,1 h,2 h,4 h,The Endocytic Pathway,Endosomes and Lysosomes,Lysosomes,
19、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，,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。
20、,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）。,Lysosomes Lysosomes are active in recycling the cells organic material and in the intracellular digestion of macromolecules. Lysosomes contain various hydrolytic enzymes that are capable of digesting nucleic acid
21、s, polysaccharides, fats and proteins. The inside of a lysosome is acidic. In humans, a variety of inherited conditions can affect lysosomes. These defects are called storage diseases. People with these disorders are missing one or more of the lysosomal hydrolytic enzymes.,动物细胞溶酶体系统示意图,Lysosome-rela
22、ted diseases,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
23、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。,The Cytoskeleton,Cytoskeleton is a network of protein filaments in the cytoplasm,Main functions: Supports large volume of the cytoplasm. Participates in large-scale movements associated with the changes in cell shape and cell motility. Provides machinery for
24、organelle transport, chromasome segregation during mitosis, and cell division.,Actin filaments,Microtubules,Intermediate filaments,Major components of cytoskeleton,The cytoskeletal filaments,Common Features : Linear polymers of protein subunits Actin ( 8 nm in diameter) Intermediate Filaments ( 10 n
25、m in diameter) Microtubules ( 24 nm in diameter) Filaments are dynamic, i.e. they can assemble and disassemble Highly conserved,Intermediate Filaments,Intermediate filaments enable cells to withstand mechanical stress when cells are stretched. They can span the entire cytoplasm and are anchored to t
26、he plasma membrane.,The Microtubule Cytoskeleton,Also penetrates the entire volume of the cell Whereas actin fibers are concentrated at the periphery, most microtubules radiate from a central location in the cell Main functions: intracellular transport and mitosis,Microtubules provide an organizatio
27、nal structure in an interphase cell and separate chromosomes in a dividing cell,http:/www.circs.neu.edu/external/Frank.Gibbons/spindle.html,Microtubules,Microtubules Provide Tracks for Transport,Microtubules are long hollow cylinders made of tubulin,Protofilaments are linear chains of tubulin dimers
28、, a parallel bundle of 13 protofilaments forms a microtubule There are three kinds of tubulins, each with many subtypes: a-tubulin and b-tubulin form a/b tubulin dimers and represent the basic building block of microtubules g-tubulin is involved in more specialized processes, such as nucleation Micr
29、otubules have a GTP “cap” stabilizing the ends.,Motor Proteins,Motor proteins bind to microtubules and move by cycles of conformational changes using energy from ATP. One end of the protein can bind to specific cellular components.,Actin is the most common protein in the cytoplasm Actin filaments ar
30、e concentrated beneath the plasma membrane and give the cell mechanical strength Assembly of actin filaments can determine cell shape and cause cell movement Association of actin filaments with myosin can form contractile structures,Actin filaments = microfilaments,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
31、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。,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。,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，
32、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。,线粒体遗传病,1894年，首次发现,1897年，正式命名为mitochondrion(线粒体),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,mtDNA的结构和遗传特
33、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(mitochondrial DNA，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。,人mtDNA是一个长为16,569 bp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,mtDNA结构紧凑，没有内含子，唯一的非编码区是D环区，长约1,000 bp左右。,D环区包括mtDNA重链复制起始点，重
34、轻链转录的启动子。,线粒体的H链是12种多肽链、12S rRNA、16S rRNA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。,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,1. mtDNA具有半自主
35、性,mtDNA的遗传学特性,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,mtDNA的母系遗传,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共存的细胞中，子细胞出现三种基因型：纯 合的突变体、纯合的正常、突变体和正常的的杂合; 3、线粒体病发病有一阈值，只有当异常的mtDNA超过阈 值才发病。女性携带者未
36、发病，但仍可以通过mtDNA 突变体向下代传递。,母系遗传的特点：,mtDNA的遗传学特征,5. mtDNA的杂质性与阈值效应,6. mtDNA的突变率和进化率极高,线粒体基因突变与线粒体基因病,对mtDNA分子病理学的研究证实mtDNA突变在许多疾病中存在，包括具有母系遗传特征的疾病，中老年时发病的一些退化性疾病，甚至衰老本身。 线粒体突变导致的疾病主要累及肌肉、中枢和外周神经系统，与贫血和糖尿病等疾病也相关。,线粒体遗传病（mitochondrial diseases） 致病基因位于线粒体基因组上，由于受精卵的 细胞质主要来自卵子，存在于细胞质中的线粒体也 来自卵子，所以线粒体遗传病表现为
37、母系遗传，即 男女均可患病，但只有女性患者的子代患病，男性 患者子代正常。,线粒体DNA的突变类型,(一) 碱基突变,也称氨基酸替换突变，主要与脑脊髓性及神经性疾病有关，常见有Leber遗传性视神经病(LHON) (MIM 535000)和神经肌病。,1. 错义突变,比错义突变的疾病表型更具有系统性特征，且所有生物合成基因突变都为tRNA突变，并与线粒体肌病相关。主要有MERRF综合征(癫痫伴碎红纤维病) (MIM 545000)。,2. 蛋白质生物合成基因突变,线粒体DNA的突变类型,mtDNA缺失突变引起绝大多数眼肌病，这种缺失导致的疾病一般无家族史。,线粒体DNA的突变类型,(二) 缺失
38、、插入突变,线粒体DNA的突变类型,(三) mtDNA拷贝数目突变： 致死性婴儿呼吸障碍 乳酸中毒或肌肉、肝肾衰竭,Leber遗传性视神经病(LHON),Leber遗传性视神经病是被证实的第一种母系遗传的疾病，至今尚未发现一个男性患者将此病传给后代。,LHON是以德国眼科医生Theodor Leber的名字命名的，为一种急性或亚急性发作的母系遗传病。男女病人比例5:1。,11778GA导致编码NADH脱氢酶亚单位4(ND4)中第340位的Arg精His组，从而影响线粒体能量的产生。,Leber遗传性视神经病(LHON),MERRF综合征,MERRF综合征是一种罕见的、杂质性的母系遗传病。,典型为8344 bp突变，即MTTK*MERRF8344G，导致tRNALys改变，使蛋白质合成受阻。,