Weeks_8_Cell_Death_2025.pdf The resources of reproduction: eggs, sperm and wombs for sale

The resources of reproduction: eggs, sperm
and wombs for sale

1. Cell Death

2. Cell death in development and adulthood
Balance between cell death and cell division→ constant total # of cells
Cell death: not arbitrary but regulated, programmed cell death; apoptosis
Morphological changes during apoptosis :
➢ shrinkage and condensation,
➢ collapse of cytoskeleton,
➢ disassembly of nuclear envelope,
➢ condensation and fragmentation of chromatids,
➢ blebbing of cell membrane,
➢ formation of apoptotic bodies,
➢ alteration of cell surface for recognition by macrophages
Cells undergo apoptosis by a highly regulated program

3. Two distinct forms of cell death
Normal cellApoptotic cellApoptotic cellNecrotic cell
Burst and spill
their content over
their neighbor→
inflammatory
response

4. Unwanted cells is eliminated by apoptosis during
development and in adulthood
Embryonic development
-Formation of hands and foot
-Metamorphosis from tadpole into frog:
tail cells undergo apoptosis and the tail
disappears
-Cell number regulation: in nervous
system
-Quality control process: elimination of
abnormal, misplaced, nonfunctional and
dangerous cells
Adulthood:
-Control of tissue/organ size through the
balance of cell death and division
-Cells with DNA damage
Apoptotic cells

5. Apoptotic cells can be biochemically characterized
Induction of both biochemical and morphological
changes
➢ Fragmentation of DNA
➢ Exposure of cleaved DNA ends→ recognized by
labeled nucleotides
➢ Exposure of phosphatidylserine to the non-cytosolic
face of the membrane ➔ recognition by Annexin V
protein
Fragmentation of DNA by
endonucleases → distinct
ladder pattern
“eat me” signal for
macrophages
Inhibition of production
of cytokines
➢ Loss of electrical potential across inner mitochondrial membrane

6. Intracellular proteolytic cascade mediated by caspases
plays role in apoptosis
Caspases:
-Conserved intracellular machinery
-Protease family with Cysteine at their active site and cleavage of target proteins at specific
aspartic acids
-Synthesized as procaspases→ activated by dimerization and proteolytic cleavage

7. Intracellular proteolytic cascade mediated by caspases
plays role in apoptosis
Initiator procaspases: cleave and activate downstream executioner procaspases
Executioner procaspases: cleave and activate other executioner procaspases and
specific target proteins, for example lamins, endonucleases, components of
cytoskeleton and cell-cell adhesion proteins
-Cell type specific caspases
-Activation of caspases:
Irreversible

8. -In healthy cells: caspase-activated DNase (CAD) kept inactive by an
inhibitor protein, iCAD.
-In the presence of apoptotic signals: Activation of an executioner caspase →
cleavage of iCAD → release of active Dnase → cutting of chromosomal
DNA b/w nucleosomes
DNA fragmentation during apoptosis

9. Cell-surface death receptors activate the extrinsic pathway
of apoptosis
Extrinsic pathway:
-Death receptors: extracellular ligand binding domain, single-pass TM domain and intracellular
death domain
-Homotrimers and belong to TNF receptor family- TNF and Fas receptors
-Ligands: homotrimers and belong to TNF family of signal proteins
Fas ligand binding to Fas
receptor
Activation of death
domain and recruitment
of FADD adaptor domain
Recruitment of initiator
procaspases to assemble
DISC (death-inducing
signaling complex)
Activation of executioner
procaspases

11. The intrinsic pathway of apoptosis is mediated by
mitochondria
Intrinsic pathway:
-Activated by injury or stress responses: DNA damage, lack of O
2, nutrients or survival signals
-Release of mitochondrial intermembrane space proteins into the cytosol→ activation of
APAF1 → recruitment of caspase-9 to form apoptosome → activation of executioner caspases
(Apoptotic protease activating factor 1)
APAF1: apoptotic peptidase activating factor 1
CARD: caspase recruitment domain

12. Bcl2 family proteins regulate the intrinsic pathway of
apoptosis
Bcl2 Family:
Regulation of cytochrome C
and other mitochondrial protein
release into the cytosol
Pro-apoptotic and anti-
apoptotic proteins, formation of
heterodimers btw pro and anti-
apoptotic proteins
Balance between the activities
of pro and anti-apoptotic
proteins→ live or die
BH domains: Bcl2 homology
domain

13. -No apoptotic stimulus:
Pro-apoptotic Bak at the outer
mitochondrial membrane
-Apoptotic stimulus: Bak oligomerizes
Apoptotic stimulus: Bak oligomerizes
→ activation of MOMP → cytochrome
C release into cytosol → assembly of
apoptosomes

Pro-apoptotic Bcl2 family effectors (Bak) induce MOMP

14. -No apoptotic stimulus:
Anti-apoptotic BclxL at the outer
mitochondrial membrane
-Apoptotic stimulus: BclxL binds to
activated Bak → blocks Bak–Bak
oligomerization, MOMP and apoptosis
Indirect effect of Bad on apoptosis:
Bad binds to anti-apoptotic BclxL →
Bak-Bak can oligomerize → induces
MOMP and apoptosis
Anti-apoptotic Bcl2 family proteins (BclxL) block MOMP

15. Inhibitor of apoptosis (IAP) and two anti-IAP proteins
help control caspase activation
How does MOMP
overcome XIAP inhibition?
XIAP inhibits initiator
caspase-9 and executioner
caspases 3 and 7→
MOMP releases two anti-
IAP proteins, Smac and
Omi→ inhibit XIAP→
activation of caspases

16. Extracellular survival factors inhibit apoptosis in
various ways
Nerve cells undergo apoptosis to adjust the number of cells during development due
to limited amount of survival signal
Overproduction + elimination = all appropriate target cells are contacted by
appropriate nerve cells +surplus nerve cells are eliminated

17. Extracellular survival factors can inhibit apoptosis

18. Extracellular survival factors can inhibit apoptosis

19. Two caspase-dependent mechanisms responsible for the
accumulation of PS on the surface of apoptotic cells

20. Either excessive or insufficient apoptosis can contribute
to disease
BH3-mimetic drug specifically inhibits anti-apoptotic Bcl2 →
prevents Bcl2 from blocking apoptosis
Venetoclax
Bcl2