Lecture 7: Irreversible effects Flashcards
2 Categories of cell death
Accidental and programmed (necrotic and apoptosis)
Apoptosis
- Part of normal physiological maintenance of organs.
- Non-inflammatory
- Requires ATP and has cascade of steps
- Single cell death
Visible by:
- cell rounding, shrinkage, fragmentation into apoptotic bodies (immune cells eat them up), DNA/chromatin condensation (pyknosis), nuclear fragmentation (karyorrhexis), membranes and organelles left intact.
Pyknosis
Chromatin/DNA condensation
(during apoptosis)
Karyorrhexis
Nuclear fragmentation
(during apoptosis)
What is apoptosis triggered by?
- Extracellular signal/ligand (FasL) binding to Fas (Death) receptors on cell membrane
- Loss of growth factors
- Detachment from ECM (anoikis), loss of function and structure - cell wonders around body - cancer.
- Oxidative stress (ROS) or ER stress
- Microtubule (important for cell division) or DNA damage
Anoikis
Detachment from ECM - loss of function and structure
How is apoptosis carried out
Smac and Cytochrome C (pro-apoptotic molecules) are released from stress induced mitochondria.
They activate APAF1 proteins to form the apoptosome complex, activating further downstream proteins - initiator caspase by oligomerisation.
Smac inhibits IAP (an anti-apoptotic caspase inhibitor). Activation of initiator and then effector caspases.
Effector caspase casues proteolytic protein cleavage, leads to apoptotic body formation. Apoptotic bodies are coated in Phosphotidyl Serine (PS), ‘eat me’ signal for phagocytes.
Once eaten, macrophages decrease TNF (pro-inflammatory), and increase TGFb (anti-inflammatory).
Tumour Necrosis Factor (TNF)
Inflammatory signal, death inducing cell signal (necrosis).
Transforming growth factor beta (TGFb)
Anti-inflammatory signal
Inadequate apoptosis
Leads to autoimmune diseases (self-reactive immune cells are not eliminated) and cancers (cell accumulation)
Excessive apoptosis
Acute ischemic injury to heart (myocardial infraction) and brain (stroke).
Chronic heart failure (cardiomyocytes) and neurodegeneration (alzheimer’s and parkinson’s).
Necrotic cell death types:
Necroptosis, Pyroptosis, Ferroptosis
Necrotic cell death:
Structural change that follows large scale cell death.
Inflammatory, emergency death caused by stressful environment. Many forms are also regulated.
ATP independent, membrane permeabilisation, and cell lysis. Sometimes visible cell swelling (oncosis), leakage of intracellular components. Repair of damaged tissue by scarring.
Oncosis
Cell Swelling
Necroptosis
‘Necro’ - death inducing protein ligands (i.e. TNF and FasL).
Receptor interacting protein kinases (RIPK) form necrosome complex, which induces oligomerisation of a protein that causes pores in the cell membrane. Resulting in leaky cell membrane.
Necrostatins
RIPK1 inhibitors that suppress cell death (preventing leaky membrane). Suppresses inflammation and loss of function.
Pyroptosis
‘pyro’ - fire. Triggered by fever or intracellular bacterial infection. Damage signals trigger inflammasomes.
Inflammasomes and caspases cleave:
Pro-IL-1b –> IL-1b –> PRO-inflammatory cytokine.
Gasdermin proteins to form pores in membranes.
Purpose: cell lysis prevents replication of intracellular bacteria and pro-inflammatory signals alert immune cells of the presence of pathogens.
Ferroptosis
‘ferro’ - triggered by ROS and iron.
Process regulated by GPX4 which uses gutathione (GSH) as a reducing agent.
p53 can induce ferroptosis by suppressing GSH synthesis.
Autophagy
Intracellular proess used to degrade intracellular pathogens, aggregated proteins, or damaged organelles.
Membrane bound vacuoles form and enclose the content, fuse with lysosomes (containing hydrolases). Vacuoles are degraded when cell is starved from nutrients to generate energy.
Phagophore (half forming vacuole) –> autophagosome (formed + lysosome –> autolysosome –> degradation.
Causes of necrosis
Ischemia, Infection, Fat necrosis.
Coagulative necrosis
- Due to ischemia
- lack of blood flow and oxygen to tissue.
- dead tissue retains its architecture becayse lysosomes don’t release their proteolytic enzymes immediately.
- necrotic tissue removed by inflammatory reaction and replaced by scar.
- could occur in heart - myocardial infarction.
Colliquative (liquefactive) - Ischemia
Cellular lysosomes are damaged and release their hydralases which digest a tissue. Tissue turns into a soft, sircumscribed (wrapped in cyst wall) lesion. Leads to a blood filled space in the damaged tissue.
i.e. cerebral artery collusion (Stroke) leading to brain ischemia.
Gas gangrene (rotting) - ischemia
Caused by deep injury trauma, damaging blood supply, leading to infection with anaerobic bacteria which can survive (doesnt need O2). Tissues feel crackly cus of CO2 produced by bacteria.
Black tissue - haemoglobin in blood is downgraded and iron sulphide is deposited. CO2 causes holes in tissue (cysts). Loss of nuclei and retention of protein, loss of architecture and function.
Dry Gangrene (mummification) - ischemia
Occurs with slow ischemia (long term). Leads to necrosis, desiccation (drying up/mummification) and discolouration from breakdown of blood.
i.e. progressive narrowing of arteries by atherosclerosis (caused by diabetes and smoking).
