Cell Death in Disease

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LASMONO SUSANTO

POSGRADUATE BIOMEDICAL SCIENCEUNIVERSITY SUMATERA UTARA

FACULTY OF MEDICINE

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apoptosis

necrosis

autophagy

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apoptosis,necrosis, and

autophagy event

mode-specific orselective

morphologic

biochemicalmolecularattributes

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cytoskeletal protein cleavage by pro-apoptotic-aspartate-specific proteases (caspases)

apoptosis

Caspase3,6,7

Caspase

9

Caspase8

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Sumber: http://science.howstuffworks.com

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1. Cell death receptor pathway (extrinsic);

Triggered by thebinding of familyof tumornecrosis factor(TNF) and TNFreceptor

formation of themulti-proteindeath-inducingsignalingcomplex (DISC)

c-FLIP is aregulatorymolecule thatresemblescaspase-8

Aggregation of the DISC

causes conformationalchanges that unleash thecatalytic activity of  caspase-8,which ediatescell destruction

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2. Mitochondrial Pathway (intrinsic).

release of pro-apoptotic

proteins from the inter-mitochondrial

membrane space into the cytosol inhibitors of apoptosisprotein (IAPs),

activation of caspasesand apoptosis

the mitochondrial apoptotic pathway controled by:• Interplay between pro- and anti-apoptotic the Bcl-2 family•

Increased ROS, DNA damage, unfolded protein response, anddeprivation of growth factors

• Caspase-9

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http://ccrc.farmasi.ugm.ac.id

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neoplasms

increasedexpression

protein Bcl-2family andmutations

defective Fasligand or Fas

receptor

the deathreceptors Fas-

mediated

autoimmunelympho-

proliferative

disease

(ALPS)

type 1

diabetes

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NMDA receptorblockade and

GABA receptoractivation BY

ETHANOL

apoptogenicneurodegenerati

on

fetalalcohol-

syndrome

Generalanesthetics ON

Neonatus

modulateNMDA and

GABAreceptors

long-termneurocognitive

defects

loss of immuneeffector cells in

sepsis

inhibits abilityto eradicatethe primary

infection

susceptible tonosocomialinfections

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redundant

damagedorganelles

macro-

molecularcomponents

Own cellnon-

essential

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autophagy

deletion of toxicmisfolded proteins

elimination

of intracellularmicroorganisms

tumorsuppression

antigenpresentation

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Procesing of autophagy

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eliminatingdamaged

mitochondriawhich may

triggerapoptosis

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Autophagy

Autophagy

loss of especially

beclin-1, UVRAG

and Bif-1

lymphomas and

gastrointestinal

tumors in mouse

models

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ischemia

metabolicfailure

Rapiddepletion of

ATP

early lossof 

plasmamembrane

Loss oforganelle

integrity

MEDIATOR NECROSIS

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http://uts.cc.utexas.edu

necrosis

calcium activated protease non-lisosomal (Calpain)poli-ADP-ribose polymerase-(PARP)

MEDIATOR NECROSIS

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type andintensity of

the signal cell

theconcentration

of ATP

cell type andother factors

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acutemyocardialischaemia

profounddecreases

in ATPnecrosis

chroniccongestive

heart failure

chronicdecreases

in ATPapoptosis

anti-apoptoticcaspaseinhibitors

hyperacuteTNF–α

necrosis

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Apoptotic cell

necrotic cell

decreased parasitemia.parasit

parasit increased parasitemia.

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peritonitis

Apoptotic cells

necrotic cells

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Cell death pathways, there are three ways:

apoptosis, autophagy and necrosis.

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Cell death is “programmed” that genetically controlled

Plasma membrane integrity is preserved until late in apoptosis BUT early lossin necrosis

Autophagy is the process to supply the cell with metabolites for fuel.

Autophagy plays a complex role in cancer

Necrosis can be regulated and programmed

Apoptotic cells and necrotic cells have on Immunomodulatory Effects

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  chard S. Hotchk ss , Andreas Strasser , Jonathan E.

McDunn, and   Paul E. Swanson,

N Engl J Med, 2009 October 15; 361(16)

References:

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