lecture 5 - Cell Death Flashcards
(24 cards)
When we say that a cell is “alive”
- Fluid & ion homeostasis
- Metabolic homeostasis
Fluid & ion homeostasis
Cells use energy to maintain their internal environment.
Usually by active transport of ions against their concentration gradient.
This also maintains water homeostasis (the cell doesn’t shrink or swell).
Metabolic homeostasis
Proteins, membranes and organelles get degraded with use
The cell uses energy to build new proteins & organelles and safely dispose of the old ones
This prevents runaway chemical reactions and leakage of enzymes between compartments
What we consider “cell death”
A cell that was previously healthy stops working as intended, and breaks down over time
Typically a result of a metabolic process, or lack thereof
If the cell dies because of an injury, it is not usually considered “cell death”
Considered cell death vs
Not considered cell death table
Cell death is a spectrum with two extremes
Cells can die in lots of ways
Necrosis: initial steps
- The cell experiences a sudden shock (example: sudden oxygen deprivation during an ischaemic stroke)
- Membrane pumps stop working and/or membrane lipids lose coherence
- Water starts rushing in and the cell swells (oncosis)
Necrosis: committed steps
- Organelles break down, releasing enzymes and other content in the cytosol
- Runaway enzymes digest more cellular components
- The cell membrane lyses, releasing the cellular content to the outside
Necrosis can affect large areas
Because the injury hit a large area (e.g. frostbite, spreading infection, obstructed blood vessel)
-AND/OR-
Because damage and inflammation spread outside of the injured area (chain reaction)
Role of immune cells in tissue healing - Under normal circumstances, dead cells are cleared up by phagocytes:
Non-inflammatory phagocytes remove apoptotic bodies (by phagocytosis)
Inflammatory phagocytes remove spilled content from necrotic cells (by pinocytosis)
If inflammation persists, it can cause further damage to the tissue and become self-sustaining (vicious cycle). This is sometimes linked to autoimmune diseases.
Apoptosis
- controlled cell death
- The cell spontaneously destroys its own organelles starting from the inside. The process is gradual and regulated.
It is usually beneficial to the organism, removing cells that are no longer needed or that have become dysfunctional.
A cell can “choose” (commit) to destroy itself because it…
detects an internal damage (such as a mutation)
is told to do so by other cells (e.g. the immune system detects that the cell is mutated/infected)
lacks the right extracellular environment (e.g. somehow ended in the wrong place)
irl apoptosis
Apoptosis is mediated by
- Caspases - are proteases (enzymes that digest other proteins)
- Exist at all times in the cell in inactive form (procaspases)
- Signal amplified through a proteolytic cascade: proapoptotic signals activate the initiator caspases, which then activate the executioner caspases
Apoptosis: initial steps
- Caspases digest the cytoskeleton, making the cell shrink, lose shape, and detach from surrounding cells & extracellular medium.
2 Caspase-activated DNAses (CADs) digest the DNA. Caspases digest the nuclear lamina, causing the separation of the nucleus in multiple pieces.
Apoptosis: late steps
- The cell membrane blebs (without lysing) and then breaks into apoptotic bodies (also without lysing). Organelles get partitioned between the apoptotic bodies.
4 Macrophages are recruited to phagocyte and digest the apoptotic bodies.
Eat me” signals
- Healthy cells have asymmetrical membranes. Flippases and floppases use ATP to transport lipids between membrane leaflets and maintain membrane asymmetry.
- Caspases inactivate flippases and floppases, and activate scramblases, which facilitate the redistribution of lipids between the outer and inner leaflet.
- Macrophages recognise exposed cytosolic lipids as “eat-me” signals, and phagocyte apoptotic bodies for recycling.
The intrinsic pathway of apoptosis
- Cellular stress (e.g. peroxide) disrupts the mitochondrial membrane
- Cytochrome C and other mitochondrial content leaks in the cytosol
- Cytochrome C activates the caspases
The extrinsic pathway of apoptosis
- A killer lymphocyte recognises a foreign antigen on the cell membrane (for example, because the cell is mutated or infected by a virus).
- The killer lymphocyte binds to the cell’s death receptor, activating the receptor’s death domain.
- This causes an intracellular signalling cascade, which ultimately activates the caspases.
You don’t need to remember the numbers of the caspases
Survival factors
Many mammalian cells (especially during development) exist in a “ready to die” state, with many procaspases in the cytosol.
These cells require survival factors (produced by themselves and/or neighbouring cells) to stay alive. In the absence of survival factors, the cell spontaneously initiates apoptosis.
A survival factor may:
Activate a protein that stabilises the mitochondrial membrane
Activate a protein that inactivates the caspases
Induce the synthesis of a protein that stabilises the mitochondrial membrane
Induce the synthesis of a protein that inactivates the caspases
Inhibit the synthesis of caspases or other pro-apoptotic proteins
…and so on and so forth.
When apoptosis goes wrong
Regulation of apoptosis…
is an area of active research!
More than 300 proteins/genes involved
Some only in some tissues
Some only in some cases
You definitely don’t need to know all of them for the exam.
However, if you want to become a researcher, you may end up working in this field - especially related to neurodegenaration.
