Mechanism of Cell Death Flashcards
Define
Etiology
Cause of a disease
Define
Pathogenesis
Biochemical and molecular mechanisms of disease development
Define
Morphology
Appearance of cells/tissues/organs
Define
Clinical Features
Manisfestation
Functional consequences of mophological changes
Lungs filled with fluid and bacteria.
What is the morphology? What are the clinical features? What is the disease?
Morphology: Fluid filled lungs
Clinical Features (functional consequence): Reduced gas exchange, shortness of breathe
Pneumonia
Why do cells die?
Lack of resources
Exposure to toxins
Removal of aging/ineffective cells
Attack by immune system
What are some events that can cause cell death due to lack of resources?
Hypoxia
Nutrient Deficiency
Growth factor withdrawal
Cellular Level: Signs of injury?
Intracellular accumulations
* Fatty deposits
* Lipofuscin
* Protein
Modes of Cell Death
Unregulated - Necrosis Signaling
Pathological
Cell breaks down/explodes and contents are released
Amount of signlaing depends on the cause
Spread/damage neighboring cells
Modes of Cell Death
Regulated - Apoptosis (multiple)
Physiological
Cell disassembles and packages contents for phagocytosis
Alternative Modes of Cell Death
Other modes besides regulated and unregulated
Necroptosis (regulated necrosis)
Anoikis (detachment-induced cell death)
Ferroptosis
What is the difference between stressed tissue and necrotic tissue?
Stressed: Blebbing, Eosinophilia, Swelling; staining variation, nuclei cluster, cells swell/rupture
Necrotic: Loss of Nuclei, Breakdown of membranes; cells have ruptured
What are the types of Necrosis?
Coagulative
Liquefactive
Caseous
Fibrinoid
Types of Necrosis: at tissue level
Coagulative
Loss of cell architecture but not tissue architecture
Types of Necrosis: at tissue level
Liquefactive
Digestion of cells results in viscous mass
Cells gone but more liquid
Types of Necrosis: at tissue level
Caseous
Fragmented cells and granular debris surrounded by inflammation
Cells gone but more solid
Types of Necrosis: at tissue level
Fibrinoid
Immune complexes and fibrin inwalls of blood vessels
Fibrin from blood gets in blood vessel wall, attaches to immune complex
Very eosinophilic staining
Causes of Necrosis
Overwhelming Damage
* Toxins
* Excessive Calcium
* Damage to ER and mitochondria
* Reactoe Oxygen Species (ROS)
* Ischemia
* Membrane damage
* Nutrient Withdrawl
Cells just fall apart
Specific instances of physiological cell death:
Immune Function
Destruction of elf-reactive lymphocytes to prevent autoimmunity
Death of cells that have served their purpose
Pyroptosis
Neutrophils die after an acute inflammatory response
Lymphocytes die at the end of an immune response
Pyroptosis - overreaction of caspases during immune function can result in cell death
Specific instances of physiological cell death:
Embryogenesis
origin of programmed cell death
Death of specific cells at specific times
During digit development
Apoptosis: Programmed Cell Death
Specific instances of physiological cell death:
- Embryogenesis
- Tissues that prduce new cells as part of their function
- Loss of hormone-dependent tissues when hormone levels fall
- Immune function
Specific instances of physiological cell death:
Tissues that produce new cells as part of their function
Immature lymphocytes in the bone marrow and thymus that fail to express useful antigen receptors
Epitherlial cells in intestinal crypts, so as to. maintain a constant number (homeostasis)
Specific instances of physiological cell death:
Loss of hormone-dependent tissues when hormone levels fall
Endometrial cell breakdown during the menstrual cycle
Ovarian follicular atresia in menopause
Apoptotic Initiators
- Viral infections
- Ionizing radiation
- Chemical damage to cells
*** Cytokines (TNF, Fas, ligand) - Mitochondrial damage**
- UPR
- Calcium influx
- Unresolved stress
Major morphological features of apoptosis
- Cell rounding/condensation
- Nuclear condensation/fragmentation
- Membrane Blebbing
- Formation of apoptotic bodies
- Nuclear condensation/fragmentation - visible with DAPI
- Membrane Blebbing - Visible with light microscopy
- Formation of apoptotic bodies - Packaging of cell contents into vesicles
Apoptosis Signaling
Extrinsic starting point of Apoptosis
Death receptors on the plasma membrane are actvivated and transduce a signal through intracellular signaling pathways to activate caspases
Initiated by things outside of the cell
Define
Apoptosis
programmed cell death
Damage but sufficent resources to manage process instead of just falling apart
Apoptosis Signaling
Intrinsic starting point of Apoptosis
Mitochondrial signals induce release of pro-apoptotic proteins that activate caspases
Initiated by things inside the cell
Damage to mitochondria can initiate
What are Caspases?
Cysteine Aspartases
Specific proteases that disasseble the cell
Biochemical markers of apoptosis
Consensus sequences: cleave after aspartic acid residue
Inflammatory: Involved with NFkB signaling
Initiator Caspases
2
8 - extrinsic
9 - intrinsic
10 - extrinsic
Executioner caspases
3
6
7
Extrinsic Apoptotic Signaling
TNF/TNFR vs. FasL/Fas
Death Domain Superfamily
Four subfamilies involved in protein complex assembly:
- Death Domain (DD) subfamily
- Death Effector Domain (DED) subfamily
- Caspase Recruitment Domain (CARD) subfamily
- Pyrin Domain (PYD) subfamily
Homotypic binding
Proteins MUST have the same domain to bind - through homotypic binding
Process to caspase activation
Initiators (autocatalytic)
Executioners (cleavage)
DED (extrinsic)
CARD (intrinsic)
Inflammation
Intrinsic Apoptotic Signaling
What are the 2 groups of the conserved domains (BH1-4) of the Bcl-2 Protein Family?
B cell lymphoma 2
Bc2 homology domains
Antiapoptotic BCL-2 Proteins
BH4-BH3-BH1-BH2-TM
Pro-apoptotic BCL-2 proteins
Effectors: BH3-BH1-BH2-TM
BH3 Only
Mitochondrial Pro-Apoptotic Factors
Activaed by caspases through tBID
How does tBid function as a mitochondrial pro-apoptotic factor?
Bid is truncated by multiple different proteases including calapins and caspases
Bid will sequester antiapoptotic BCL-2 family members or activate pro-apoptotic members (Bax and Bak)
Apoptosome formation
Types of Failed stress response
p53-induced cell death (DNA damage, genotoxic stress)
ER stress/UPR - halts protein translation and upregulated chaperone expression
Calcium signaling
What is the function of p53?
anti-oncogene
Critical in DNA damage repair
Transcription Factor
Negative regulators of cell cycle progression
promotes apoptosis
What happens if p53 is unbalanced?
Underexpression - increases cancer susceptibility
Overexpression - promotes aging
PIDDosome
p53-induced death domain
Define
ER Stress
accumulation of misfolded proteins
Define
Unfolded Protein Response
Stress response that promotes degredation of proteins and increased chaperone production to improve folding
How does the ER participate in death signaling?
Release of ER calcium can prime mitochondria (intrinsic pathway)
ER propagates death-inducing stress signals through Bcl-2 family members
ER stress-induced cell death contributes to:
Fas-induced cell death (BAP31 cleavage by Caspase 8)
p53-induced cell death
What are the effects of cellular calcium?
Overload of cellular calcium is a known factor of necrosis
homeostasis is effected by Bcl-2 family
Calcium Toxicity
ER calcium depletion…
induces UPR
Calcium Toxicity
ER calcium release…
may activate specific enzymes
Calpain (protease) - Bid/Bax/Bcl-2 cleavege; Cadpase 12 activation
Calcineurin (phosphatase) - bad dephosphorylation
Calcium Toxicity
Excessive mitochondrial calcium…
Impairs mitochondrial function (depolarization)
Increased ROS generation
Induces release of proapoptic factors
