Lecture 6: Cell injury - reversible effects Flashcards
Physical Damage to DNA
Ionising Radiation (free radicals interfere with DNA causing DNA strands to break), UV radiation (cross linking of pyrimidines)
Chemical damage to DNA
Alkylation (i.e. aflatoxin B1) - binds and modifies DNA structure, G -> T transversions.
Biological damage to DNA
Dietary Deficiency (i.e. folic acid - B4, Cobalamin - B12) - necessary for DNA synthesis or repair, essential for making Thiamine and methionine (start AA).
Physical damage to lipids
Crystals
Chemical damage to lipids
Oxidants - ROS
Biological damage to lipids
Lipases - i.e. organ damage due to leakage of phospholipases
Physical damage to proteins
Heat - denatured proteins, activate heat shock proteins (chaperones) to stop aggregation of proteins, restructure proteins, and reintroduce the unction of those proteins. If not possible, tag for destruction
Chemical damage to proteins
Glycation (addition of sugar to proteins) -> malliard reaction
D-glucose + primary amine –> Schiff base –> Amadori product –> Advanced glycation end (AGE) product.
Accumulation of AGE causes proteins to not function properly.
Biological damage to proteins
Proteases (i.e. inflammation)
proteases released during inflammation, cleave specific structural proteins.
i.e. Arthritis: accumulation of proteases that cleave collagen in joints
i.e. Emphysema: accumulation of proteases that cleave elastin in lung ECM
i.e. Cancer invasion: “ “ “ cleave laminin, allowing cancer cells to migrate, change shape, location, and function of cells.
ROS functions
- Mitochondria reduce O2 to ROS as a part of respiration (ETC), and are essential intermediates in other enzyme reactions
- neutrophils release ROS to kill bacteria.
- React with lipids and proteins within cell and cause cell death.
- act as signalling molecules to promote DNA replication and proliferation.
How does ROS injure cell?
- Hydroxyl radicals react with lipid hydrogens to cause lipid peroxidation (modification of hydrogen groups, issues with membrane structure).
Membrane structure:
- increased rigidity (no longer malleable)
- decreased activity of protein enzymes (i.e. sodium pumps).
- altered activity of membrane receptors.
- make cells leaky (increased membrane permeability).
- O2 therapy in babies leads to lung damage
- Inflammation mediated by macrophages and neutrophils
- UV radiation excites molecules, transferring energy to O2, causing skin damage
- Ionising radiation includes hydroxyl radiation.
AGE (Advanced glycation end) product
- Inhibits protein function
- causes proteins to cross-link, making them insoluble/precipitate.
- generates ROS (thus interfering with lipids and proteins too).
- binds to cell surface receptors (RAGE), and signals cause blood flow and inflammation.
- accumulates in diabetes (more sugar available)
- cardiovascular disease
-neurodegeneration in brain (i.e. alzheimers) through insoluble proteins blocking neural function - cataract in lens through protein deposition.
What are the reversible injuries/effects through which cells can adapt, survive, and recover?
Acute intracellular oedema (hydropic change, cell swelling).
Abnormal storage (fatty acids)
Response to stress
Acute intracellular oedema
Injury due to increased P.M. permeability (i.e. lipid peroxidation - ROS).
NA/K pump ATPase damaged, ATP synthesis disrupted in mitochondria. ATPase reduces activity.
K+ leaks out of the cell and Na+ into the cell, osmotic gradient balance, cells and organelles visibly reduce swelling.
If swelling is excessive, cell death mechanism.
Abnormal storage
Cell cannot process molecules, causing accumulation of fats and glycogen. i.e. Steatosis - ^storage of fats in hepatocytes.
Diabetes: ^conc of fatty acids from adipose tissue
Alcohol: damaged hepatocyte mitochondria’s ability to breakdown TGC (fats).
Kwashiorkor: malnutrition due to inability to transport TGC as VLDL.
Adaptive response to stress
Respond differently as per stressor - which bind to receptor, enabling transcription of genes.
Inducer of stresses: DNA Damage Response (DDR), Proteotoxic (heat shock), Hypoxia, Antioxidant response, Unfolded protein response (UPR).
Adaptive response to stressor: DNA Damage Response (DDR)
Transcription factor - p53 detects breaks in DNA strands and induces DNA repair to occur before mitosis and S phase (dna synthesis).
Failure to repair DNA can lead to cell death - apoptosis.
Adaptive response to stressor: Proteotoxic response (heat shock)
Triggered by accumulation of unfolded, denatured, aggregated proteins. Transcription factor HSF1 activates transcription of chaperone proteins and HSP (heat shock proteins) which:
- promote folding of denatured proteins
- target damaged proteins for destruction
- prevent protein aggregation which is cytotoxic.
Adaptive response to stressor: Hypoxia
Transcription factor: HIFa, induced by low O2. Induces proteins active in glucose transport and glycolysis, RBC production, Blood vessel production (VEGF).
Process supports capacity of O2 transfer on RBC, and create new B.V. to transport blood to ischaemic/hypoxic tissues.
Adaptive response to stressor: Antioxidant response
Triggered through detection of oxidative stress and regulation of ROS to upregulate antioxidant enzymes to rebalance redox homeostasis.
Adaptive response to stressor: Unfolded protein response (UPR)
Triggered by unfolded/denatured proteins in ER. Induces production of chaperones, suppresses global protein synthesis, induces ERAD (ER-associated degradation), promotes autophagy to eliminate aggregated proteins.
