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Cellular Pathology > CELL DEATH - APOPTOSIS > Flashcards

CELL DEATH - APOPTOSIS Flashcards

1
Q

List the forms of programmed cell death

A 
1- Autophagy
2- Apoptosis
3- Necroptosis
4- Pyroptosis
5- Necrosis/Oncosis
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2
Q

Descibed in general apoptosis

A

1• Apoptosis tightly regulated suicide program that depend on an intracellular proteolytic cascade that is mediated caspases
2• Activation of enzymes degrading DNA and proteins
3• Formation of apoptotic bodies with membrane
4• Discovered in 1972
5• Name means “falling off”

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3
Q

Explain the causes of Apoptosis

A

Physiologic Situations
1• Embryogenesis
2• Involution of hormone-­dependent tissues upon hormone withdrawal
3• Cell loss in proliferating cell populations
4• Elimination of potentially harmful self-­reactive lymphocytes
5• Death of neutrophils in an acute inflammatory
response
6• Death of lymphocytes at the end of an immune response

Pathologic Conditions
1• DNA damage
2• Accumulation of misfolded proteins
3• Cell death in certain infections

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4
Q

Describe the morphological changes in apoptosis

A

1• Cell shrinkage (opposite to swelling)
2• Chromatin condensation into dense masses of various shapes and size
3• Formation of cytoplasmic blebs and apoptotic bodies.

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5
Q

Describe the characteristical biochemical changes in cells undergoing apoptosis

A
  1. Chromosomal DNA cleaved into fragments
  2. Change in the plasma membrane –
    phosphatidylserine
    in the outer leaflet
  3. Loss of electrical potential across the inner
    membrane of the mitochondria
  4. Relocation of cytochrome c from the
    intermembrane space of the mitochondria to
    the cytosol
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6
Q

State the functions of Caspases

A

1) Involved in inflammation:
- Caspases 1(ICE), 4, 5

2) Caspases involved in apoptosis
- Initiator caspases: caspases 2, 8(eDRP), 9(iMP), 10
- Executioner caspases: caspases 3, 6, 7

3) Target paroteins:
- Nuclear lamins
- Protein that holds the endonuclease in an inactive state
- Components of the cytoskeleton and cell-­cell adhesion proteins

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7
Q

Explain the phases of apoptosis

A

1• Initiation phase:
- activation of caspases (cysteine proteases that cleave proteins after aspartic residues) normally present as proenzymes
2• Execution phase:
- other caspases trigger the degradation of critical cellular components.

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8
Q

Explain the pathways (mechanism) of Apoptosis

A

1- Intrinsic Mitochondrial Pathway

2- Extrinsic Death receptor pathway

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9
Q

Describe the intrinsic mitochondrial pathway

A

1• Major mechanism of apoptosis in all mammalian cells
2• Due to increased permeability of the mitochondrial outer
membrane with consequent release of death-­inducing (pro-­
apoptotic) molecules from the mitochondrial intermembrane
space into the cytoplasm
3• cytochrome c released into the cytoplasm initiate the suicide
program of apoptosis
4• controlled by the BCL2 (B cell lymphoma) family of proteins

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10
Q

Classify the BCL family

A

1• Anti-­apoptotic

  • BCL2, BCL-­XL, and MCL1
  • 4 BCL2 homology (BH) domains (called BH1-­4)
  • Keep the mitochondrial outer membrane impermeable

2• Pro-­apoptotic

  • BAX and BAK
  • 4 BH domains
  • Oligomerize and form a channel

3• Sensors

  • BAD, BIM, BID, Puma, and Noxa
  • 1 BH domain (called BH3-­only proteins)
  • sensors of cellular stress and damage
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11
Q

Explain the Mechanism of the intrinsic mitochondrial pathway

A
  1. DNA damage and misfolded proteins induce ER stress
  2. Sensors (BH3-­only proteins) “sense” such damage and are activated
  3. Sensors bind to and block the function of BCL2 and BCL-­XL (anti-­apoptotic)
  4. Activation of BAX and BAK (pro-­apoptotic)
  5. Leaking of protein in the cytoplasm
  6. Cytochrome c binds to a protein called APAF-­1 (apoptosis-­activating factor-­1) to hydrolyse bound dATP to dADP
  7. Formation of a mulitmeric structure called the apoptosome triggered by the release of dADP in exchange for dATP (or ATP)
  8. The complex binds and activates caspase-­9,
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12
Q

Explain the extrinsic death receptor-intitiated pathway

A

1• Death receptors
members of the TNF receptor family
type 1 TNF receptor (TNFR1) and Fas (CD95)
cytoplasmic domain called the death domain

2• Fas
expressed on many cell types
3 or more molecules of Fas are binding site for FADD
(Fas-­associated death domain).
FADD binds an inactive form of caspase-­8 and 10
Inhibited by a protein called FLIP
Some viruses and normal cells produce FLIP to protect
themselves from Fas-­mediated apoptosis.

3• FasL expressed by cytotoxic T cells and by T cells
recognizing autoantigens

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13
Q

Explain the multiple roles of TNF: apoptosis and inflammation

A

1) Inflammation
1- NFk-B
2- p38

2) Apoptosis
1- Caspase pathway

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14
Q

Explain the execution phase of Apoptosis

A

1• mitochondrial pathway activate initiator caspase-­9
2• death receptor pathway activate initiator caspase-­8
3• rapid and sequential activation of the executioner caspases.
4• caspase-­3 and -­7, act on many cellular components.
5• cleave an inhibitor of a cytoplasmic Dnase
6• Caspases also degrade structural components of the
nuclear matrix and thus promote fragmentation of nuclei.

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15
Q

Explain the removal of dead cells

A

1• Cells that are dying by apoptosis secrete soluble
actors that recruit phagocytes

2• Phosphatidylserine “flips” out and is expressed on the
outer layer of the membrane and is recognized by several macrophage receptors

3• Other eat me signals are coating with proteins of the
complement system, notably C1q, which are recognized
by phagocytes

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16
Q

What are the pathologies of Apoptosis?

A

1) Tissue Atrophy
1• Neurodegenerative diseases, loss of specific sets of neurons, in which
apoptosis is caused by mutations and misfolded proteins
2• Ischemic injury, as in myocardial infarction and stroke
3• Death of virus-­infected cells in many viral infections

2) Hyperplasis
1• Mutations in TP53, defective DNA repair, accumulation of mutations, cancer.
2• Failure to eliminate potentially harmful cells, such as lymphocytes that can
react against self antigens
3• Failure to eliminate dead cells, a potential source of self antigens
4• Atherosclerosis

17
Q

Elaborate the pathoilogical role of apoptosis in neurodegeneration

A

1- Neurons are post-­mitotic (cannot replace
themselves;; neuronal stem cell replacement is
inefficient)

2- Neuronal death caused by loss of proper
connections, loss of proper growth factors (e.g.
NGF), and/or damage (especially oxidative
damage)

3- Neuronal dysfunction or damage results in loss
of synapses or loss of cell bodies
(synaptosis, can be reversible;; apoptosis,
irreversible)

18
Q

Types of neurodegeneration and their causes

A

PARKINSON’S DISEASE

  • Apoptosis of dopamine neurons in the substantia nigra
  • Dopamine is given to prevent apoptosis

ALZHEIMER’S DISEASE
- Apoptosis of neurons in the hippocampus and certain regions of the cerebral cortex

HUNTINGTON’S DISEASE
- Apoptosis of neurons in the striatum

AMYOTROPHIC LATERAL SCLEROSIS
- Apoptosis of lower motor neuron

19
Q

What are the anti-apoptotic therapy in diseases

A

Aim of the treatment in neurodenerative diseases is to block apoptotic triggers and activation of anti-apoptotic pathway

1- Stimulation of IAP - for treatment of stroke, spinal chord injury, multiple sclerosis

2- Synthetic nonspecific caspase inhibitors - trials going on treatment of myocardial reperfusion injury, RA

20
Q

Elaborate the relationship of apoptosis with Cancer

A

Apoptosis eliminates damaged cells
(damage => mutations => cancer)

Tumor suppressor p53 controls senescence
and apoptosis responses to damage

Most cancer cells are defective in apoptotic response
(damaged, mutant cells survive)

High levels of anti-­apoptotic proteins
or
Low levels of pro-­apoptotic proteins
===> CANCER

21
Q

What are the causes of dysregulated of apoptosis and cancer?

A

1- Impaired receptor signalling pathway

2- Disrupted balance of the BCL-2 family of proteins

3- Increased expression of IAPs

4- Reduced expression of caspases

5- Defect/mutation in p53

22
Q

Describe Necroptosis

A

1• Shares aspects of both necrosis and apoptosis

2• Morphologically resembles necrosis

  • loss of ATP
  • swelling of the cell and organelles
  • generation of ROS
  • release of lysosomal enzymes
  • rupture of the plasma membrane

3• Mechanistically similar to apoptosis (genetically programmed)

4• “Caspase-­independent” programmed cell death

5• Defense mechanism against certain viruses that encode caspase inhibitors (e.g.,cytomegalovirus)allowing the cell to undergo “cellular suicide” in a caspase-independent fashion.

6• In addition to being a response to disease, necroptosis has also been characterized as a component of
inflammatory diseases such as Crohn’s disease, pancreatitis, myocardial infarction and neurodegenerative diseases (Parkinson).

23
Q

Explain the mechanism of necroptosis

A

1• Ligation of TNFR1, Fas, and other sensors of viral DNA
and RNA

2• Recruitment of two kinases called receptor associated
kinase 1 and 3 (RIP1 and RIP3)

3• Formation of a complex

4• Permeabilization of lysosomal membranes

5• Generation of ROS

6• Damage of mitochondria

7• Reduction of ATP

24
Q

Describe PYROPTOSIS

A

1• Cell death accompanied by the release of fever
inducing cytokine IL-­1

2• Activated by microbial products that enter the cytoplasm (in order to kill them)

3• Activation of the inflammasome

4• Activation of caspase-­1

5• Cleavage of a precursor form of IL-­1

6• Induction of fever

7• Induction of cell death

25
Q

Comparison between pyroptosis and apoptosis

A 
Similarities
1-DNA fragmentation
2- Nuclear condensation
3- PARP1 cleavage
4- Caspase 3 and 7 activation
Differences
Pyroptosis
1- Release of intracellular contents
2- Membrane vesicle formation
3- Membrane swelling
4- Membrane rupture
5- Cytosolic swelling

Apoptosis
1- Apoptotic body formation
2- Preservation of membrane integrity
Cytoslic shrinkage

26
Q

Describe Autophagy

A

1• Autophagy is a process in which a cell eats its own contents

2• (Greek: auto, self;; phagy, eating).

3• Delivery of cytoplasmic materials to the lysosome

4• Evolutionarily conserved survival mechanism in states
of nutrient deprivation (cannibalization for recycling of digested molecules)

5• Implicated in:

  1. physiologic states: housekeeping role in removing misfolded or aggregated proteins, clearing damaged organelles, such as mitochondria, endoplasmic reticulum and peroxisomes, as well as eliminating intracellular pathogens
  2. pathologic processes: cancer, neurodegenerative diseases

6• Deregulation has been linked to non-­apoptotic cell death

27
Q

Explain the mechanism of autophagy

A

1- Vesicle nucleation - Formation of an isolation membrane (derived from the ER)
2- Vesicle elongation ( Nucleation and elongation of the vesicle = formation of autophagosome)
3- Docking and fusion - fusion with lysosomes
4- Vesicle breakdown and degradation - Degradation of the contents

28
Q

Role of autophagy in the promotion and suppression of cancer

A

Promotion of cancer

  • Increase in the resistance of apoptosis
  • Increase in cell survival during therapy
  • Increase in cell survival during nutrient shortage

Suppression of cancer

  • Decrease of ROS, DNA damage
  • Increase in autophagic cell death
  • Induction of apoptosis-
  • Decrease in necrosis and inflammation
  • Decrease in cell proliferation

Cellular Pathology (5 decks)

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