Apoptosis: Cell Death-PDF

APOPTOSIS “Cell Death” 193 Apoptosis or programmed cell death, is carefully coordinated collapse of cell, protein degradation , DNA fragmentation followed by rapid engulfment of corpses by neighbouring cells. (Tommi, 2002) Essential part of life for every multicellul...

APOPTOSIS “Cell Death” 193 Apoptosis or programmed cell death, is carefully coordinated collapse of cell, protein degradation , DNA fragmentation followed by rapid engulfment of corpses by neighbouring cells. (Tommi, 2002) Essential part of life for every multicellular organism from worms to humans. (Faddy et al.,1992) Apoptosis plays a major role from embryonic development to senescence. 194  Why should a cell commit suicide? Apoptosis is needed for proper development Examples: – The resorption of the tadpole tail – The formation of the fingers and toes of the fetus – The sloughing off of the inner lining of the uterus – The formation of the proper connections between neurons in the brain Apoptosis is needed to destroy cells Examples: – Cells infected with viruses – Cells of the immune system – Cells with DNA damage – Cancer cells 195 196 197 What makes a cell decide to commit suicide? Withdrawal of positive signals examples : – growth factors for neurons – Interleukin-2 (IL-2) Receipt of negative signals examples : – increased levels of oxidants within the cell (ROS) – damage to DNA by oxidants – death activators : Tumor necrosis factor alpha (TNF-a) Lymphotoxin (TNF-β) Fas ligand (FasL) 198  Necrosis vs. Apoptosis Necrosis Apoptosis Cellular swelling Cellular condensation Membranes are broken Membranes remain intact ATP is depleted Requires ATP Cell lyses, eliciting an Cell is phagocytosed, no tissue inflammatory reaction reaction DNA fragmentation is Ladder-like DNA fragmentation random, or smeared In vivo, individual cells appear In vivo, whole areas of the affected tissue are affected 199 200  Cascade of Cellular Events In apoptosis, a cascade of events comes into play to remove a cell. In early stages, a set of enzymes called caspases begin to work. These proteins break apart the scaffold within the cell. In turn, caspases activate enzymes that take apart DNA. The cell at this point is visibly undergoing self destruction, as can be viewed through a microscope. Its shape changes, matching the biochemical changes taking place inside. As the cell skeleton is disassembled, the cytoplasm shrinks. The nucleus also shrivels. Various characteristics of apoptosis show that this process is underway. These apoptotic markers allow investigators to see clearly that apoptosis is the cause of cell death. Aside from the biochemical cascade within the cell, visible signs of an apoptotic cell include broken off bits of the membrane, and small vesicles called apoptotic bodies. Changes at the cell surface of an apoptotic cell meanwhile signal the macrophages to come and engulf it. This clean removal of the cell avoids the inflammatory problems of necrosis. 201  What is a Caspase? Caspases are a family of cysteine proteases whose functions are inextricably linked with the process of programmed cell death, or apoptosis Cysteine proteases, also known as thiol proteases, are enzymes that degrade proteins (Verma et al., 2016). 202  Extracellular activation A killer lymphocyte carrying the Fas ligand (Death ligand)binds and activates Fas proteins (Death Receptors)on the surface of the target cell. Adaptor proteins bind to the intracellular region of aggregated Fas proteins, causing the aggregation of procaspase-8 molecules. These then cleave one another to initiate the caspase cascade. 203 204  Two Caspase Pathways Extrinsic Pathway  Death Ligand  Death Receptors  Caspases  Cell Death 205  Intracellular activation In this pathway, a variety of apoptotic stimuli cause cytochrome c release from mitochondria. Apoptosis regulator (BAX) translocates to the mitochondria and forms foci whereas Cyt c is released from the mitochondria into the cytosol. Mitochondria release cytochrome c, which binds to and causes the aggregation of the adaptor protein Apaf-1. Apaf-1 binds and aggregates procaspase-9 molecules, which leads to the cleavage of these molecules and the triggering of a caspase cascade. Other proteins that contribute to apoptosis are also released from the mitochondrial intermembrane space 206 207  Two Caspase Pathways Intrinsic Pathway  Mitochondria  Cytochrome C  Apoptosome Complex  Caspases  Cell Death 208