Apoptosis general description
Regulated cell suicide
Via intrinsic enzymes —> acting on DNA, nuclear and cytoplasmic proteins.
—> then forms ‘apoptotic bodies’ = cytoplasm and nucleus—> these are easy targets for phagocytosis
List 5 situations of apoptosis in physiological situations
- Embryogenesis —> different phases
- Growth factor deprivation —> cells which are sensitive to hormone stimulation do not receive the hormones they need undergo apoptosis- (eg Lymphocytes: antigens + cytokines / neurons: nerve growth factor
3 Cell loss in proliferating cell population: —> eg lymphocytes in the bone marrow and thymus
- Elimination of self-reactive lymphocytes
- Death of host cells that have served their purpose —> eg neutrophils after acute inflammatory response and lymphocytes after immune response
List three apoptosis in pathological conditions
- DNA damage from (radiation, cytotoxic anticancer drugs and hypoxia), If repair mechanism cannot cope with injury —> ‘tumour-suppressor gene p53 induces apoptosis’
- Accumulation of misfiled proteins: ( from mutations in the genes encoding the proteins or extrinsic factors (free radicals) = apoptosis via the proteins accumulating on ER = the condition called ER stress —> apoptosis cell death
- Infections, in particular viral infections
Explain apoptotic cell death histologically morphologically
Process of creating apoptotic bodies
- condensation and fragmentation of the nucleus (Pyknosis and karyorrhexis)
- Blebbing of the plasma membrane (the cell’s cytoskeleton breaks up and causes the membrane to bulge outward)
Thus histologically apoptotic cells appear
- round or oval mass
- Intensely eosinophilic cytoplasm with fragments of dense nuclear chromatin
Mechanisms of apoptosis
- caspases enzyme activation = cleave proteins apart
- Proenzyme caspases —> activated caspases = two pathways
a) mitochondrial pathway
b) Death receptor pathway
Explain the mitochondrial pathway
major pathway
Increased mitochondrial membrane permeability = pro-apoptotic molecules releasing from inter membrane space into —> cytoplasm
BCL2 family proteins control release of pro-apoptotic proteins = three families of molecules
Anti-apoptotic
Pro-apoptotic
Sensors
Explain anti-apoptotic molecules
Lx = outer mitochondrial membranes, cytosol + ER membranes
Fx= keeping mitochondrial outer membrane impermeable = prevent leakage of cytochrome C and other death-inducing proteins into cytosol
Explain pro-apoptotic molecules
Fx = when activated
oligomerise (combine together like Voltron) with outer mitochondria membrane = promoting increase in mitochondrial outer permeability
Explain Sensor molecules
Fx = sense cellular stress + damage
= regulate balance between anti-apoptotic and pro apoptotic
What stimulates the production of anti-apoptotic proteins?
Growth factors and other survival signals
When and how do pro-apoptotic proteins activate?
cells deprived of survival signals
DNA is damaged
Misfolded proteins induce —> ER stress
The things above activate the sensor molecules which in turn activate the pro-apoptotic proteins.
Important note - sensors may also bind to + block anti-apoptotic proteins.
Net result =
- increased permeability of mitochondria outer membrane —> allowing mitochondria proteins that can activate the caspase cascade.
Explain the extrinsic pathway of apoptosis
Plasma membrane death receptors
Present on variety of cells
Best known receptor = type 1 TNF receptors and Fas
Fas Ligand on T cells attaches to Fas receptor = forming a binding site for an adaptor protein called FADD which activate intracytoplasmic Caspases
Explain the final phase of apoptosis
Both pathways converge here
DNA cleavage + degradation
Disorders associated with dysregulated apoptosis
“Too little or too much”
Too little = too many abnormal cells survive = cancer
Or lymphocytes which react to self- antigens are not apoptosised = autoimmune disorders
Increased apoptosis
neurodegenerative disease
Ischaemic injury
Death of virus-infected cells
