APOPTOSIS

What's the difference between apoptosis and necrosis?

First things first both processes lead to cell death, but the first one is a programmed
death , the second one occurs in case of problems for the cells, so it's a response to a
particular situation.
Necrosis:Accidental cell death Response to a wide variety of pathogenic noxae
(hypoxia, hyperthermia, ischemia, etc.).
Apoptosis:Programmed cell death or "cell suicide" Physiological process triggered by
pathological factors .
Apoptosis
• Apoptosis is the programmed cell death
• it's a physiological process
• occurs in single cells
• it's activated by the caspase (cysteine protease)
• it doesn't occurs in case of inflammation
• we have the shrinking of the cell followed by the fragmention and
formation of apoptotic bodies

In which cases does it occurs?

Apoptosis pathway
It's a cascade of events. Everything starts with the activation of the Caspase (group of
cysteine proteases that are activated at an early stage of apoptosis and are responsible
for triggering most of the changes observed during cell death).Now Apoptosis can be
triggered by both internal stimuli and external stimuli,external stimuli activate the
extrinsic pathway, that is distinct from that utilized by internal stimuli, which is called
the intrinsic pathway.
Extrinsic pathway

As we can see in the image above, we need two iniziator pro-caspase to get the
executioner caspase ( the active one which will initiates apoptosis ).
• the stimulus for apoptosis is carried by an extracellular messenger protein
called tumor necrosis factor (TNF)
• then we need receptors for this signal, the main one is FAS which posses a
Death domain.
• when a TNF binds its receptor (like FAS) this will undergo a
conformational change of the death domain activating it.
• The activation of the death domain will cause the recruitment of FADD (FAS
associated protein with death domain).
• Then FADD associates with pro-caspase8 ( it's the most common one) via
dimerization activating it, getting thus the active Caspase-8.
( when two procaspases are held in close association with one another, they are
capable of cleaving one another’s
polypeptide chain and converting
the other molecule to the fully active
caspase. )
• Caspase 8 (initiator) will
activate caspase 3,6,7 (executioner)
which will induce apoptosis by causing
the nucleus and cytoskeleton to break.

Intrinsic (mitochondrial) pathway

Activation of the intrinsic pathway is regulated by members of the Bcl-2 family of
proteins, which are characterized by the presence of one or more small BH domains.
Bcl-2 family members can be subdivided into three groups:
(1)Proapoptotic members, that promote apoptosis (Bax and Bak)
(2)Antiapoptotic members ,that protect cells from apoptosis (Bcl-2, Bcl-X)
(3)BH3-only proteins , which promote apoptosis by an indirect mechanism
(BIM,BAD,BID)

Everything here is regulated by P53 which will activate BH3- only proteins. In some
cases they promote apoptosis by inhibiting antiapoptotic Bcl-2 members, whereas in
other cases they promote apoptosis by activating proapoptotic Bax or Bak. In case of
certain types of stress the BH3-only proteins are expressed or activated, thereby
shifting the balance in the direction of apoptosis so that the effects of the
antiapoptotic Bcl-2 proteins are overridden. Now what happens is that:
• Firstly the BH3-only proteins inhibits the antiapoptotic Bcl-2 members and
activate the proapoptotic memebers(Bax,Bak).
• Bax and Bak which are permanent residents of the outer-mitochondrial
membrane (OMM) undergo a change in conformation that causes them to assemble
into channel within the OMM.
• Once formed, this channel dramatically increases the permeability of the OMM
and promotes the release of mitochondrial proteins,cytochrome c .
• Once in the cytosol, the cytochrome c molecules form a multisubunit
complex,called apoptosome, with a cytosolic protein called Apaf-1 and procaspase-9
molecules.
• Procaspase-9 molecules are activated as the result of a conformational change
induced by association with Apaf-1,thus getting the active Caspase-9
• Caspase-9 (initiator) will activate Caspase-3 or 6 ( executioner) which will
induce apoptosis.
Necrosis
Necrosis is characterized by the swelling of both the cell and its internal
membranous organelles, membrane breakdown, leakage of cell contents into the
medium, and the resulting induction of inflammation.
The sequence of events that occur in a cell that is dying from necrosis may vary
depending on the tissue and the type of damage; however, regardless of the order this
is what happens in a cell going into necrosis:
• ATP production stops.
• The membrane ion pumps become blocked.
• Sodium and water enter the cell.
• The cell and internal organelles swell.
• The cell initiates the response with increased synthesis of chaperonins that
attempt to counteract protein denaturation and ubiquitin (protein that covalently
binds denatured proteins and directs them to destruction).
• pH decreases.
• Calcium enters the cell.
• Calcium activates phospholipases that cause the loss of phospholipids from
membranes and the formation of lysophospholipids and fatty acids that induce further
membrane damage.
• Calcium activates CALPAINS, proteases that damage cytoskeletal
structures and membrane proteins resulting in vesiculation.
• Calcium activates ATPases causing further loss of ATP.
• Calcium activates endonucleases.
• The response can no longer counteract the protein denaturation that becomes
massive.
• The RE and other organelles swell and at some point the cell dies.