Detailed notes from the lectures in the master course BMS37 Cell death in life and disease. So instead of rewatching 12 hours of lectures, you can read this, which saves time when preparing for the exam ;)
MED-BMS37: Cell death in life and disease
Lecture 1: Cell stress a cause of disease
Stress
- stress originates in cells and will affect function of tissue and ultimately affect the
function of the whole organism
Definitions of cell stress
- = Alterations in the internal and external cell environment
- mechanical stress; wound
- infection
- inflammation
- hyperthermia; proteins and enzymes denature and coagulate. leaky blood
vessels because endothelial cells get affected by heat → blisters
- hypothermia; mitochondria affected → ATP lower
- toxins
- storage disorders (genetic mutations)
- energy shortage (hypoxia, mitochondrial disorders, diet)
Reaction to stress on tissue/cell level
- adaptation possible → cell survival
- adaptation impossible → cell death
- apoptosis
- necrosis
- necroptosis
- ferroptosis
- autophagy; not directly to cell death, cells start to eat their own organelles,
occurs under cell stress (i.e. nutrient deprivation), it may not lead to cell death
- pyroptosis; inflammation related
- inflammation is involved in a lot of these processes
- or cell becomes senescence (between survival and death → (zombie
cell)
- complete block of proliferation, do not function anymore and
are a burden to the body
Cellular responses to stress
- adaptation possible → cell survival
- atrophy; reduction in size and function of cell
- use them or lose them (muscle cells in cast for 6 weeks will crease in
size but not in number)
- hypertrophy; increase in cell size and function
- i.e. in the heart, often occurring in atherosclerosis
- hyperplasia; increase in cell number
- metaplasia; change in differentiation state
- example; barrett's esophagus
- cells differentiate in glandular cells to make mucus to protect
the cell from acid reflux
- squamous cells die from low pH → inflammation
- goes in hand with hyperplasia because these glandular cells
are like the ones we have in the intestine and proliferate very
, fast in combination with inflammation→ increases risk of
cancer
- dysplasia; disorganized tissue structure
CONCEPT; labile, stabile, and permanent cells
- G0 phase = rest
- G1 phase followed by S phase if cell can divide
- labile cell/tissue = more than 1.5 are actively in the cell cycle i.e. intestinal cells/
bone marrow cells → need to continuously repopulate
- damage in cell and recognized by p53 → DNA repair mechanisms, not completed?
→ apoptosis
- stable cell (quiescent) = able to proliferate, but only if there is a need. i.e.
hepatocytes, endothelial cells in blood vessels
- normally in G0 but can go in G1
- permanent cells = continuously in G0 phase and cannot enter in G1. i.e neurons
Senescence;
caused by:
- aging (oxidative stress)
- replicative stress (telomere shortening)
- telomerase enzyme can repair this shortening to a certain extend
- oncogene activation/ defective apoptotic signaling
- SASP production
- large amount of senescent cells in body, experience continues low
inflammation
The cell cycle in cancer
Cancer is a process of uncontrolled cell proliferation
1. Check on cell cycle distrubed p53/ RB system
2. Regulation of apoptosis is disturbed Bcl system, role of mitochondria
3. Metabolism is disrupted VHL, IDH
,Cell cycle visualization; Cdt1 is expressed in G1 but degraded by geminin from S-phase on
- Cdt1 normally keeps complex stable with double helix DNa
- onset of S phase, geminin comes in and ubiquilinate Cdt1
- geminin can set on other processes to replicated DNa
- Cdt1 degraded in S-phase by geminin
- FUCCI Cdt1-orange/geminin green → G1 phase = red, S-M phase = green
Epigenetic modification: HDAC (histone deacetylation) inhibitors
- HDAC → makes chromatin structure more compact
, - for certain diseases HDAC inhibitor drugs are made → leads to
hyperacetylation of genes. Induce proliferate → mitotic stress (because
proliferation costs ATP and there will not be enough for the cell to survive)
- HATs (histone acetyltransferases) → make chromatin more loose
ROS; electron transport in mitochondria: O2 → H2 O
- ROS are created in the ETC
- electrons can leak
- electrons are transported to oxygen to produce water (in OXPHOS)
- O2 needs to transfer 4 electrons to form 2 H2O
- catalase can neutralize hydrogen peroxide into water
- vitamin E and C are antioxidants that can help remove the radicals
Hemochromatosis; iron storage disease due to HFe mutation
- dysregulated Fe uptake
- dysregulated hepcidin expression
- no stop on iron intake (macrophages, intestines)
iron is taken up via the diet and comes in via the gut → Fe(III) transformed to Fe(II) via vit c.
Then gut epithelium can take it up. Hefestin oxidizes Fe(II) to Fe(III). Fe(III) is present in
blood and will be transported to places in the body where iron is needed.
- mutation in iron uptake
- hepcidin = hormone that regulates iron uptake
- hepcidin reduced, increased in iron uptake in blood and organs overall
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