Summary cell death in pathofyiology H1-5

H1: CELLULAR STRESS RESPONSES: A SNAPSHOT
1.1 WHAT IS STRESS? GOOD OR BAD?

1.1.1 FRUIT FLY EXPERIMENT

Experiment
= they created a mutant with an overexpression of Hsp60
●​ Because of this the mitochondria experience stress
●​ They expected that the flies would be in trouble, but they observed the
opposite = flies live longer

Explanation
= if you are daily exposed to stress = the mitochondria are in stress
→ defense mechanisms are upregulated → they deal better with the stress → live longer




1.2 WHAT IS CELLULAR STRESS?

1.2.1 DIFFERENT FORMS

Different forms of cellular stress
●​ DNA damage
●​ Oxidative stress
●​ Metabolic stress
●​ Pathogens
●​ Senescence
●​ Heat
●​ …

,1.3 HOW TO DEAL WITH CELLULAR STRESS?

1.3.1 SIMPLIFIED SNAPSHOT

How we could look at how a cell is dealing with stress
= overview of what this course is about


PHASE 1 Cellular repair mechanisms
= The first thing a cell does when it is exposed to stress
●​ There are different mechanisms of a cell to deal with damage
●​ Depending on which kind of stress, you use another mechanism
○​ DNA damage response (DDR)
○​ Unfolded protein response (UPR)
○​ Heat shock response (HSR)
○​ Oxidative stress response
○​ Autophagy

= When the cell succeeds you go back to homeostasis
= If you can not fix it (too much damage) the cell can decide to die or to freeze


PHASE 2 Cell death
= In case the damage could not be fixed with cellular repair mechanisms
= This dead cell needs to be cleaned → phagocytosis = innate immunity

= Once the cell is gone, you will go back into homeostasis
= If the cells don’t manage to clean everything in time you reach inflammation


Cellular senescence
= Cell freezes and will lose it’s functioning
●​ The cell will stay in its place
●​ This way the structure of the organ is remained


PHASE 3 Inflammation
= Help from IS to remove danger
●​ No clearance of the cellular stress = disease

= You can go back to homeostasis
= Incase the inflammation isn’t resolved, you can develop a bunch of diseases

,H2: CELLULAR STRESS RESPONSES
2.0 IMPORTANT

2.0.1 EXAM

There will be no open question coming from chapter 2,3 and 4 → only MCQ and terminology
There will be also MCQ and terminology coming from other chapters.



2.0.2 IMPORTANT


KEEP IN MIND

Always keep this figure in mind = simplified picture that summarizes this course




TYPICAL EXAM QUESTIONS

1)​ What is BER, MMR, HDR, NER,...
2)​ What is ionizing radiation doing

, 2.1 DNA DAMAGE RESPONSE (DDR)

2.1.1 DIFFERENT TYPES OF DNA DAMAGE & REPAIR

Background
Our DNA library will be copied many times → there will be many mistakes → this needs to be
repaired = 15 billion repairs in human body
●​ You want this repair mechanism to work well
●​ There will be different types of DNA repair mechanisms based on the damage



Different types of DNA repair mechanisms


DNA REPAIR MECHANISM DNA DAMAGE

Mismatch repair (MMR) Damage due to replication errors
●​ Base mismatch
●​ Bulges (uitstulping): an extra/missing nucleotide on one strand


Bases excision repair (BER) Damage due to reactive oxygen species (ROS)
●​ Single-strand break (SSB)

Damage due to oxidation, alkylation and hydrolysis
●​ Single base damage


Non-homologous end joining (NHEJ) Damage due to ionizing radiation
Homology-directed repair (HDR) ●​ Double strand breaks

Damage due to chemotherapeutics
●​ Interstrand crosslinks


Nucleotide excision repair (NER) Damage due to chemotherapeutics
●​ Interstrand crosslinks

Damage due to UV light and radicals
●​ Intrastrand crosslinks
●​ Bulky adducts