Apoptosis

what are the different forms of cell death

-necrosis

-apoptosis

-excitotoxicity

what is necrosis

-traumatic cell death

what is apoptosis

-involves activation of death programme

what is excitotoxicity

-specialised form of cell death confined to neural tissue

what are the causes of necrosis

-injury/insult from ischemia or hypoxia

what are the causes of apoptosis

-withdrawal of growth factors

-chemotherapy

-contact with cytotoxic T cells

-following a developmental programme

how to cytotoxic T cells cause apoptosis

-when cancer/infected cells present antigens on surface

-they are recognised by cytotoxic T cells

-contact between them activates apoptotic pathway

-also can release perforin which forms pored on membrane of target cell

-disturbs cell homeostasis and causes necrosis

what happens to the membrane in necrosis

-gets damages

what happens to the membrane in apoptosis

-membrane intact with blebbing

what is blebbing

-when cytoskeleton separates from cell membrane

-causing membrane to form spherical protrusions

what happens to the chromatin in necrosis

-chromatin flocculation

-clumping or aggregation of chromatin within nucleus

what happens to the chromatin in apoptosis

-chromatin condensation

what happens to energy levels in necrosis

-energy levels rapidly deplete -

what happens to energy levels in apoptosis

-energy levels are maintained

-or slowly deplete

do the cellular contents leak in necrosis

yes

do the cellular contents leak in apoptosis

-no

is there an inflammatory response in necrosis

-no

is there an inflammatory response in apoptosis

-no

-apoptotic cells are rapidly engulfed by phagocytes

what are the stages of apoptosis

-chromatin condensation

-membrane blebbing

-cell fragmentation into apoptotic bodies

-phagocytosis

what is the significance of cell being engulfed after programmed cell death

-prevents release of intracellular molecules

-important in nervous system

-release of excitotoxic mediators from dying cells can cause injury to adjacent neurons

why cells commit apoptosis

-cells infected with virus

-cancer cells

-cells bearing excessive DNA damage

-to promote self tolerance

what happens to DNA in apoptosis

-endonuclease cleaves the DNA that connects 1 nucleosome to the next

how do apoptotic cells attract phagocytes

-release find me signals which attract motile phagocytes

-display phosphatidylserine on their outer membrane

-receptors on phagocytes bind to this which stimulates them to release anti inflammatory cytokines

-then engulfment of dying cell

-engulfed corpse goes through series of phagosome maturation

-leading to degradation

what happens to membrane potential during apoptosis

-apoptotic cells lose electrochemical potential

-that exists across inner mito membrane

-causing change in membrane potential

what evidence shows that apoptosis has been conserved across much of eukaryotic lineage

-same genes that control apoptosis in simple work have genes in humans that perform the same function

-eg: caspase gene

what are caspases

-proteases that drive apoptosis

what is the structure of caspase

-have cysteine at active site

-cleave their substances at aspartic site

what are the 2 apoptotic pathways

-extrinsic

-intrinsic

what is the extrinsic apoptotic pathway

-responding to extracellular signals

-indicates that a specific cells is no longer needed for well being of organism

-involves transmembrane death receptors

-members of tumor necrosis factor (TNF) receptor superfamily

what is the function of TNF receptor superfamily

-bind to extrinsic ligands

-then transduce intercellular signals that activate caspases

what is the intrinsic pathway

-apoptotic stimuli cause mito membrane to become leaky

-leads to release of cytochrome c into cyto

-which activate caspase

what is the intrinsic pathway responsive to

-cytotoxic drugs that have entered the cell

-DNA damage; if damage cant be repaired

why does body dispose of cells if damage cant be repaired

-could become a tumour cells

-threaten whole organism

what diseases are caused by excessive apoptosis

-heart attacks & strokes feature loss of cells by apoptosis

-type I diabetes is caused by apoptosis of pancreatic B cells

what diseases are caused by insufficient apoptosis

-autoimmune disease; large number of lymphocytes in spleen and lymph glands

-stimulating loss of cell by apoptosis limits extent of reaction

-cancer; if not activated in tumour cells could lead to cancer

what is excitotoxicity

-when excessive glutamate acts on an excitatory receptors

-causing cell death

how is glutamate synthesised

-from precursor in krebs cycle, then taken up by exocytic vesicle

-after being used as neurotransmitter recycled

how is glutamate synthesised after being used as neurotransmitter

-nerve terminals and glial cells reuptake released glutamate

-via membrane transporters

-in glia glutamate is converted to glutamine

-glutamine is transported into neuronal terminals via transporters in glial and neuronal terminal membranes

-in neuronal terminal glutamine is converted into glutamate

-this is then taken up into vesicle and stored

-released by exocytosis

what are the dangers of excitotoxicity

-during hypoxia or hypoglycaemia excess glutamate is released into extracellular space

-causing prolonged activation of glutamate receptors on neighbouring neurons; killing them

how does prolonged activation of glutamate receptors kill neighbouring neurons

-glutamate binds to AMPA receptors; let Na+ into cell

-depolarising the membrane

-NMDA receptors are double gated; req glutamate and depolarisation to open

-normally Mg2+ blocks it

-depolarisation dislodges Mg allowing Ca to flood in through NMDA receptors

-causing prolonged CA entry

why is CA overload destructive

-excess Ca activates Ca dependant enzyme that break down cells components

-activates enzymes that produce reactive oxygen species

-causing further oxidative damage

what disorders is excitotoxicity associated with

-stroke

-trauma

-epilepsy

-huntingtons

-parkinsons

-alzheimers