细胞凋亡的线粒体途径.ppt
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1、细胞凋亡的线粒体途径,蒋舜媛 董霞 程在全 2002-12-17,报告提纲,细胞凋亡的特征,细胞死亡,损伤性死亡 Necrosis 程序化死亡、细胞凋亡 Programmed Cell Death Apoptosis,细胞凋亡的特征,形态学特征: 染色质的凝集, 嗜碱性染色增强, 细胞核崩解此时线粒体保持形态正常. 细胞体积缩小,一部分细胞质和核碎片进入由膜包被的程序死亡小体,他们从细胞表面出芽脱落,并被巨噬细胞.上皮细胞吞噬.,生化特征: 染色质降解, 核小体间连接DNA部位被降解,产生寡聚核小体DNA片段,即180-200DP 整数倍的不同长度的DNA片断.,Fig.1. Schemati
2、c summary of biochemical mechanisms of apoptosis.,Mitochondria and Commitment to Cell Death,线粒体是真核细胞的重要细胞器,是动物细胞生成ATP的主要地点。 线粒体基质的三羧酸循环酶系通过底物脱氢氧化生成NADH。NADH通过线粒体内膜呼吸链氧化。 与此同时,导致跨膜质子移位形成跨膜质子梯度和/或跨膜电位。 线粒体内膜上的ATP合成酶利用跨膜质子梯度能量合成ATP。 合成的ATP通过线粒体内膜ADP/ATP载体与细胞质中ADP交换进入细胞质,参与细胞的各种需能过程。,Mitochondria and Co
3、mmitment to Cell Death,the effectors of apoptosis are represented by a family of intracellular cysteine proteases known as caspases. Inhibiting caspases, however, does not always inhibit cell death induced by proapoptotic stimuli. Although caspase inhibitors block some or all of the apoptotic morpho
4、logy induced by growth factor withdrawal, etoposide, actinomycin D, ultraviolet (UV) radiation, staurosporine, enforced c-Myc expression, or glucocorticoids, they do not necessarily maintain replicative or clonogenic potential; ultimately, the cells die despite inactivation of caspases by way of a s
5、lower, nonapoptotic cell death (6-9).,In contrast, antiapoptotic proteins such as Bcl-2, Bcl-xL, and oncogenic Abl can maintain survival and clonogenicity in the face of these treatments. Conversely, some proapoptotic proteins such as Bax, a mammalian cell death protein that targets mitochondrial me
6、mbranes, can induce mitochondrial damage and cell death even when caspases are inactivated (10). Such experimental observations argue that a caspase-independent mechanism for commitment to death exists. This mechanism is likely to involve mitochondria, as we will see.,Mitochondrial Pathways in physi
7、ological cell death,the release of caspase activators (such as cytochrome c), changes in electron transport, loss of mitochondrial transmembrane potential, altered cellular oxidation-reduction, participation of pro- and antiapoptotic Bcl-2 family proteins.,Mitochondrial Pathways in physiological cel
8、l death,If mitochondria are pivotal in controlling cell life and death, then how do these organelles kill? At least three general mechanisms are known, and their effects may be interrelated, including,(i) disruption of electron transport, oxidative phosphorylation, and adenosine triphosphate (ATP) p
9、roduction; (ii) release of proteins that trigger activation of caspase family proteases; and (iii) alteration of cellular reduction-oxidation (redox) potential,Disruption of electron transport and energy metabolism,disruption of electron transport has been recognized as an early feature of cell deat
10、h. -Irradiation induces apoptosis in thymocytes and a disruption in the electron transport chain, probably at the cytochrome b-c1/cytochrome c (cyto c) step. Ceramide (a “second messenger“ implicated in apoptosis signaling) disrupts electron transport at the same step in cells as well as in isolated
11、 mitochondria. Ligation of Fas also leads to a disruption in cyto c function in electron transport.,Disruption of electron transport and energy metabolism,One consequence of the loss of electron transport should be a drop in ATP production. Although such a drop has been observed during apoptosis, it
12、 often occurs relatively late in the process (14). Indeed, ATP appears to be required for downstream events in apoptosis (15). Thus, although loss of mitochondrial ATP production can kill a cell, it is unlikely that this is a mechanism for induction of apoptosis.,Disruption of electron transport and
13、 energy metabolism,线粒体跨膜电位的耗散与细胞凋亡有密切关系 近年来陆续有报道说明线粒体跨膜电位的耗散早于核酸酶的激活,也早于磷酯酰丝氨酸暴露于细胞表面。而一旦线粒体跨膜电位耗散,细胞就会进入不可逆的凋亡过程。线粒体解联的呼吸链会产生大量活性氧,氧化线粒体内膜上的心磷脂。实验证明,用解偶联剂mClCCP会导致淋巴细胞凋亡。而如果能稳定线粒体跨膜电位就能防止细胞凋亡。,Release of caspase-activating proteins,The importance of mitochondria in apoptosis was suggested by studie
14、s with a cell-free system in which spontaneous, Bcl-2-inhibitable nuclear condensation and DNA fragmentation were found to be dependent on the presence of mitochondria (16). Subsequently, studies in another cell-free system showed that induction of caspase activation by addition of deoxyadenosine tr
15、iphosphate depended on the presence of cyto c released from mitochondria during extract preparation (17). During apoptosis (in vitro and in vivo) cyto c is released from mitochondria and this is inhibited by the presence of Bcl-2 on these organelles (18, 19). Cytosolic cyto c forms an essential part
16、 of the vertebrate “apoptosome,“ which is composed of cyto c, Apaf-1, and procaspase-9 (20). The result is activation of caspase-9, which then processes and activates other caspases to orchestrate the biochemical execution of cells.,Release of caspase-activating proteins,Significantly, caspase inhib
17、itors do not prevent cyto c release induced by several apoptogenic agents, including UV irradiation, staurosporine, and overexpression of Bax (14, 21, 22). An exception is cyto c release from mitochondria induced by the tumor necrosis factor receptor family member Fas, in which cyto c release is pre
18、vented by inhibition of caspases (primarily caspase-8) recruited to the cytosolic domain of ligated Fas (21). Nevertheless, cyto c release can sometimes contribute to Fas-mediated apoptosis by amplifying the effects of caspase-8 on activation of downstream caspases (23). The emergent view is that on
19、ce cyto c is released, this commits the cell to die by either a rapid apoptotic mechanism involving Apaf-1-mediated caspase activation or a slower necrotic process due to collapse of electron transport, which occurs when cyto c is depleted from mitochondria, resulting in a variety of deleterious seq
20、uelae including generation of oxygen free radicals and decreased production of ATP,Reactive oxygen species and cellular redox.,Mitochondria are the major source of superoxide anion production in cells. During transfer of electrons to molecular oxygen, an estimated 1 to 5% of electrons in the respira
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