Cell Death: Chapter 23, Lippincott Illustrated Reviews, PDF

Cell death Chapter 23 Introduction to Cell Death - All cells eventually die by either necrosis or apoptosis. - Necrosis: Passive, pathological process. Induced by cellular injury or accidental means. Often involves the simultaneous death of groups of cells. Necroti...

Cell death Chapter 23 Introduction to Cell Death - All cells eventually die by either necrosis or apoptosis. - Necrosis: Passive, pathological process. Induced by cellular injury or accidental means. Often involves the simultaneous death of groups of cells. Necrotic cells have ruptured cell membranes. Cytoplasm and organelles spill into surrounding tissue fluids. Often induces an inflammatory response. - Apoptosis: Active, normal, physiological process. Removes individual cells without damaging neighboring cells or inducing inflammation. Cells have a characteristic "blebbed" appearance of their membranes. Fundamental to cellular and tissue physiology, akin to cell division and differentiation. Disturbances in apoptosis pathways may lead to cancers, autoimmune diseases, and neurodegenerative disorders. Necrosis Passive, pathological process Induced by Acute injury or disease Characteristics: Affects groups of cells in a localized region simultaneously. Cells increase in volume and lyse (burst). Release of intracellular contents, including mitochondria. Often induces a damaging inflammatory response. Necrotic process completes within several days. Apoptosis Programmed cell death (apoptosis) is an active, physiological process. Deprivation of survival factors activates the suicide program. Ensures cells live only when and where needed.  Apoptosis Characteristics Cell Shrinkage: Cells shrink but do not lyse. Plasma membrane remains intact but portions bud off (blebbing). Phosphatidylserine in the Inner membrane phospholipid flips to cell surface by scramblase, which serves as an "eat-me" signal to phagocytic cells Mitochondria releases cytochrome c in an ATP-dependent process but remain within blebs. Chromatin segments and condenses.  Apoptosis Characteristics Apoptotic bodies are formed from apoptotic cells and engulfed by phagocytic cells (e.g., macrophages, dendritic cells). Apoptotic bodies are recognized for engulfment by the presence of phosphatidylserine. Scramblase removes the membrane phospholipids phosphatidylserine from the inner membrane leaflet. Phagocytic cells also release cytokines including interleukin-10 (IL-10) and transforming growth factor (TGF-β) that inhibit inflammation. Apoptosis is completed within a few hours. Biological Significance of Apoptosis 1- Removal of damaged cells Removes cells damaged beyond repair, infected, or starved by saving nutrition and viruses from spread. p53 protein halts cell cycle and stimulates apoptosis. Biological Significance of Apoptosis 2- During development Extensive cell division and differentiation during the development of embryo often result in an excess number of cells that must be removed in order for normal development to proceed and for normal function to occur. More than half of the nerve cells in the vertebrate nervous system undergo programmed cell death soon after they are formed. Selective apoptosis "sculpts" the developing tissues. E.g. apoptotic death of cells between developing digits must occur for formation of individual fingers and toes. Incomplete apoptosis can result in abnormal structures. Biological Significance of Apoptosis 2- For tissue homeostasis Balance between cell division and death maintains constant cell number. Initiation of apoptosis 1- Apoptosome (Internal Cell Death Program) Initiated by irreparable damage to cellular components or DNA. Bax (proapoptotic protein, Bcl-2 family) is inserted into the mitochondrial membrane allowing cytochrome c exits mitochondria into the cytoplasm. Cytochrome c in the cytosol triggers the formation of Apoptosome using ATP. Cytoplasmic cytochrome c activates the apoptotic protease activating factor (Apaf-1) adaptor protein that in turn activates caspase 9. Active caspase 9 initiates the caspase proteolytic cascade that will cleave and destroy cellular proteins and DNA in order to cause cell death by apoptosis. Initiation of apoptosis 1- Apoptosome (Internal Cell Death Program) Initiation of apoptosis 2- Death receptor (External Cell Death Program) Triggered by death receptors (e.g., Fas, TNFR). The tumor necrosis factor receptor (TNFR) recognizes specific ligands. TNFR possess a homologous cytoplasmic sequence termed the "death domain (DD)”. Adaptor molecules such as FADD (Fas- associated death domain) and TRADD (TNFR- associated protein) contain such DDs. They interact with the death receptors to transmit the apoptotic signal to the death machinery, via Initiation of apoptosis 2- Death receptor (External Cell Death Program) The Fas death receptor is a member of the TNFR superfamily that will initiate apoptotic cell death when engaged by the Fas ligand (Fasl). T-cytotoxic cells express Fasl that interacts with the Fas death receptor on host cells infected with virus in order to stimulate their apoptotic death. TNFR1 is also involved in death signaling, but its death-inducing capability is weak compared to that of Fas (CD95). Initiation of apoptosis Caspase family of proteases The caspase family of proteases will be stimulated to actually degrade cellular components in the apoptotic cell. Caspases are proteases that are major effectors of apoptotic cell death. They are members of the cysteine protease class. Caspases are synthesized as inactive zymogen or proenzyme forms and are activated to become functional proteases when needed. This posttranslational modification ensures that the enzymes can be activated rapidly when required in an apoptotic cell. Caspase family of proteases Classification of caspases Caspases are grouped based on their function Initiator caspases cleave inactive proenzyme forms of effector caspases, resulting in their activation. Effector caspases "executioner caspases" proteolytically cleave protein substrates with the cell, causing the apoptotic demise of the cell. Caspase family of proteases The caspase cascade: This process is the sequential proteolytic activation of one caspase after another in an orderly fashion during the initiation of apoptosis. Caspase inhibitors regulate the process. The cascade can be activated by various stimuli, 1- Apoptosome. 2- Death receptors. 3- Granzyme B released by cytotoxic T cells.