Chapter 2 Part 3 Flashcards
Define apoptosis
pathway of cell death that is induced by tightly regulated suicide program in which cells destined to die activate intrinsic enzymes that degrade the cells’ own nuclear and cytoplasmic proteins
When does apoptosis occur as a physiological condition?
- destruction of cells during embryogenesis
- involution of hormone-dependent tissues upon hormone withdrawal
- cell loss in proliferating cell populations
- elimination of potentially harmful self-reactive lymphocytes
- death of host cells that have served their useful purpose
When does apoptosis occur in a pathologic condition?
- DNA damage
- accumulation of misfiled proteins
- cell death in certain infections
- pathologic atrophy in parenchymal organs after duct obstruction
Morphologic features associated with apoptosis
- cell shrinkage
- chromatin condensation
- formation of cytoplasmic blebs and apoptotic bodies
- phagocytosis of apoptotic cell or cell bodies, usually by macrophages
Apoptosis results from the activation of…
caspases (cysteine proteases that cleave proteins after aspartic residues)
What two phases are the process of apoptosis divided into?
1) initiation phase- during which some caspases becomes catalytically active
2) execution phase- during which other caspases trigger the degradation of critical cellular components
What two distinct pathways converge on caspase activation?
1) mitochondrial pathway
2) death receptor pathway
What occurs during the mitochondrial (intrinsic) pathway?
-results from increased permeability of the mitochondrial outer membrane with consequent release of death inducing (pro-apoptotic) molecules from the mitochondrial inter membrane space into the cytoplasm
What controls the release of mitochondrial pro-apoptotic proteins?
BCL2 family of proteins
What are the 3 groups the BCL family is divided into?
1) anti-apoptotic: BCL2, BCL-XL, MCL1
2) pro-apoptotic: BAX and BAK
3) Sensors: BAD, BIM, BID, Puma, Noxa
Anti-apoptotic protein functions
keep mitochondrial outer membrane impermeable and prevent leakage of cytochrome c and other death inducing proteins into cytosol
Pro-apoptotic protein functions
promote outer mitochondrial membrane permeability allowing the leakage of cytochrome c from the inter membranous space
Function of sensors
sensors of cellular stress and damage, regulate the balance between the other two groups
What does cytochrome c bind to once released into the cytosol?
APAF-1 (apoptosis activating factor 1) forming a multimeric structure called the apoptosome
What does the apoptosome complex do?
bind caspase 9 to initiate the mitochondrial pathway and sets up an auto amplification process
Mitochondrial (intrinsic) pathway overview
1) cell injury (growth factor withdrawal, DNA damage, protein misfolding)
2) triggers BCL2 family sensors
3) signal BCL2 effectors (BAX and BAK) to promote membrane permeability
4) release of cytochrome c and other pro-apoptotic proteins from the mitochondria
5) singnals initiator caspases (formation of apoptosome)
6) executioner caspases either activate endonucleases leading to nuclear fragmentation of breakdown the cytoskeleton
7) formation of cytoplasmic bleb
8) cytoplasmic bleb becomes apoptotic body
9) apoptotic body binds to phagocytic cell receptors
How is cell viability maintained?
1) survival signal (growth factor) binds to receptor protein
2) production of anti-apoptotic proteins (BCL2, BCL-XL)
3) no leakage of cytochrome c
How is the extrinsic (death receptor initiated) pathway initiated?
engagement of plasma membrane death receptors on a variety of cells
Describe the interactions that occurs during the activation of the extrinsic pathway of apoptosis
1) FasL expressed in T cells binds to Fas, which is a death receptor expressed in many cell types
2) 3 or more molecules of Fas are brought together and their cytoplasmic death domains form a binding site for FADD (Fas-associated death domain)
3) FADD attached to the death receptor binds an inactive caspase-8
4) multiple pro-caspase-8 molecules are brought into close proximity and cleave one another to generate active caspase 8
5) follow the rest of the mitochondrial pathway
What protein inhibits the extrinsic pathway?
FLIP- binds to pro-caspase-8 but cannot activate it
The mitochondrial pathway leads to an activation of what caspase?
9
The death receptor pathway leads to an activation of what caspases?
8 and 10
What are the two executioners caspases?
3 and 6
What are examples of changes that occur in the membranes of apoptotic cells and fragments to promote phagocytosis?
- phosphatidylserine flips to outer leaflet
- secretion of soluble factors that recruit phagocytes
- coated with thrombospondin
- coated with natural antibodies and proteins of complement system (C1q)
What accumulates in cells when DNA is damaged?
p53; arrests cell cycle at G1 phase to allow for time to repair
What does p53 do if damage is too great to be repaired successfully?
triggers apoptosis
What control the proper folding of newly-synthesized proteins
chaperones in the ER
What happens with mid folded polypeptides?
ubiquitinated and targeted for proteolysis in proteosomes
Unfolded protein response
buildup of unfolded or misfiled proteins that accumulate in the ER; activates pathways that increase production of chaperones, enhance degradation of abnormal proteins, and slow protein translation
Cytotoxic T Lymphocyte Mediated Apoptosis
recognize foreign antigens on surface of host cells and secrete perforin to promote entry go granzymes; granzymes activate variety of cellular caspases and induce effector phase of apoptosis
Examples of disorders associated with defective apoptosis and increased cell survival
- cancer (mutations in TP53)
- autoimmune disorders (failure to eliminate harmful cells)
Examples of disorder associated with increased apoptosis and excessive cell death
- neurodegenerative diseases
- ischemic injury
- death of virus infected cells
How is necroptosis similar to necrosis?
morphologically; loss of ATP, swelling of cell and organelles, generation of ROS, release of lysosomal enzymes and rupture of plasma membrane
How is necroptosis similar to apoptosis?
mechanistically; triggered by genetically programmed signal transduction events that culminate in cell death
How does necroptosis differ from apoptosis in its activation?
does not result in caspase activation
Necroptosis overview
1) linking of TNFR1 receptor with ligand TNF
2) recruitment of RIP1-RIP2 complex
3) failure to activate caspase 8
4) formation of necrosome
5) metabolic alterations leading to decreased ATP and increased ROS
6) bioenergetic breakdown, protein oxidation, DNA damage
7) loss of cell and organelle integrity
8) cell death
Cystic Fibrosis
Protein: CFTR
Pathogenesis: loss of CFTR leads to defects in chloride transport
Familial Hypercholesterolemia
Protein: LDL receptor
Pathogenesis: loss of LDL receptor leading to hypercholesterolemia
Tay-Sachs Disease
Protein: Hexosaminidase B subunit
Pathogenesis: lack of lysosomal enzyme leads to storage of GM2 gangliosides in neurons
Alpha 1- antitrypsin deficiency
Protein: a1-antitrypisin
Pathogenesis: storage of non-functional protein in hepatocytes causes apoptosis; absence of enzymatic activity in lungs causes destruction of elastic tissue giving rise to emphysema
Creutzfeld-Jacob Disease
Proteins: prions
Pathogenesis: abnormal folding of PrPsc causes neuronal cell death
Alzheimer Disease
Protein: AB peptide
Pathogenesis: abnormal folding of AB peptides causes aggregation within neurons and apoptosis
