Apoptosis membrane alterations

Once apoptosis is triggered, a stereotyped sequence of premitochondrial events occurs that executes the cell death process. In many cases proteins and/or lipid mediators that induce changes in mitochondrial membrane permeability and calcium regulation are produced or activated. For example, the pro-apoptotic Bcl-2 family members Bax, Bad and Bid may associate with the mitochondrial membrane and modify its permeability. Membrane-derived lipid mediators such as ceramide and 4-hydroxynonenal can also induce mitochondrial membrane alterations that are critical for the execution of apoptosis. 

Changes occur at the cell surface and plasma membrane in the early stages of apoptosis. One of the major plasma membrane alterations is the translocation of phosphatidylserine (PS) from the inner side of the plasma membrane to the outer layer for external exposure (FI). This change of exposure requires the activation of caspase-3, a Ca flux over the plasma membrane, and a change in Bcl-2 family (B8,B13, M6). 

Merocyanine 540 is a red-emitting fluorescent dye that appears to be a sensitive measure of apoptosis-induced alterations in cytoplasmic membrane lipid structure (68). In apoptotic cells, the fluorescence increases in some models increased fluorescence correlates well with increased annexin V binding (68,71). Merocyanine 540 staining has been successfully used together with Hoechst 33342 to identify cell-cycle specific apoptotic events (72). 

In the early stages of apoptosis, plasma membrane alterations occur at the cell surface, and PS translocates from the inner side to the outer layer of the plasma membrane. PS and phosphatidylethanolamine are actively confined to the inner cytofacial leaflet of the plasma membrane by the aminophospholipid translocase. This has been identified as a trigger for stimulation of the phagocytosis of apoptotic cells by macrophages, thus preventing secondary necrosis and inflammation of the surrounding tissue. 

Mitochondrial permeability transition involves the opening of a larger channel in the inner mitochondrial membrane leading to free radical generation, release of calcium into the cytosol and caspase activation. These alterations in mitochondrial permeability lead eventually to disruption of the respiratory chain and dqDletion of ATP. This in turn leads to release of soluble intramito-chondrial membrane proteins such as cytochrome C and apoptosis-inducing factor, which results in apoptosis. 

The involvement of mitochondria in the pro-apoptotic effects of carotenoids has been clearly demonstrated by the fact that P-carotene induces the release of cytochrome c from mitochondria and alters the mitochondrial membrane potential (Aym) in different tumor cells (Palozza et al., 2003a). Moreover, the highly polar xanthophyll neoxanthin has been reported to induce apoptosis in colon cancer cells by a mechanism that involves its accumulation into the mitochondria and a consequent loss of mitochondrial transmembrane potential and releas of cytochrome c and apoptosis-inducing factor (Terasaki et al., 2007). 

During apoptosis, the mitochondrial permeability is altered and apoptosis-specific protease activators are released from this organelle. The discontinuity of the outer mitochondrial membrane results in the release of cytochrome C to the cytosol followed by subsequent depolarization of the inner mitochondrial membrane (C5, PI). The release of cytochrome C further promotes activation of cas-pases, which are important molecules for initiating apoptosis (T6). Apoptosis inducing factor (AIF), another molecule released into the cytoplasm, has proteolytic activity and is by itself sufficient to induce apoptosis. 

Injury to cell plasma membrane can activate acid sphingomyelinase to break down membrane lipid sphingomyelin and generate the second messenger ceramide, a complex lipid, to initiate the apoptosis (HI). Ceramide, perhaps through intracellular mitogen-activated protein kinases (MAPK), can alter cellular susceptibility to TNF-a, FasL, and ionizing radiation-induced apoptosis (HI, Wll). 

T5. Thornberry, N. A., andLazebnik, Y, Caspases Enemies within. SciencelSl, 1312—1316(1998). T6. Tsujimoto, Y., and Shimizu, S., Bcl-2 family Life-or-death switch. FEBSLett. 466,6-10 (2000). V1. Van den Eijnde, S. M., Boshart, L., Reutelingsperger, C. R, De Zeeuw, C. I., and Vermeij-Keers, C., Phosphatidylserine plasma membrane asymmetry in vivo A pancellular phenomenon which alters during apoptosis. Cell Death Differ. 4, 311-316 (1997). 

In summary, autoantibodies can be internalized into living cells of various types via various receptors on the cell membrane. Then these antibodies travel to different localizations and react with various target antigens. Finally, the functions of cells are altered by induced apoptosis or augment inflammation. 

CVB3 pathogenesis is complex and results in many changes to the host cell, known collectively as cytopathic effects (Carthy et al. 1998, 2003). Such changes include cell rounding, detachment from substrate, altered membrane permeability, and membrane fusion. Eventually these lead to lysis of host cells mainly through apoptosis or necrosis. Inhibition of host transcription and translation, and loss of cellular homeostasis due to direct viral protease cleavage of structural proteins such as dystrophin likely contribute to the cellular structure disruption and death of infected cells . 

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