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The Molecular Mechanisms of Apoptosis
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General introduction of the programmed cell death (PCD)
Definition of apoptosis
The evolutionarily conserved apoptotic pathway
The historical view of apoptosis
The origin and evolution of PCD/apoptosis: the
evidence and theory
Outline
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Programmed cell death (PCD)
A genetically controlled cell suicide
Often occurs at a specific point in development
Include apoptosis and non-apoptosis
non-apoptosis: autophagy-induced cell death,
necroptosis, PARP1-mediated cell death,
entosis, pyroptosis
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Non-apoptotic PCD
Pyroptosis: caspase 1-dependent cell death
Necroptosis : RIP1 kinase-dependent necrosis
Entosis: cell death as a result of becoming
engulfed by a neighboring cell
PARP-1-mediated cell death: PARP-1-
dependent but caspase-independent cell death
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Autophagy: self-eating
Cell Cycle 2010, 9:17, 3470-3478
Autophagy-induced cell death
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Introduction to apoptosis
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Apoptosis, one of the PCD,
describes the orchestrated collapse
of a cell, staging membrane
blebbing, cell shrinkage, protein
fragmentation, chromatin
condensation and DNA degradation
followed by rapid engulfment of
corpses by neighboring cells
Nature 407 12 October 2000
Apoptosis (Greek, falling away)
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The highly conserved apoptotic pathway
Apoptosis Dec 24, 2009
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Apoptosis:
a historical view
In 1800s
Normal cell death observed during amphibian metamorphosis
Observation of epithelial lining of regressive ovarian
follicles with broken nuclei which eventually disappear
In 1914
Gapher proposed that there must be an amitotic mechanism to
counterbalance mitosis
In 1951
Glucksmann described physiological cell death in the embryo
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Apoptosis:
a historical view
In 1960
Concept of cell suicide emerged; individual cell death for
the benefit of the whole organism
In 1964, Lockshin and Williams
Programmed cell death used to describe the cell deaths
that occur in predictable places and at predictable times
during development
In 1972, Kerr, Wyllie, and Currie
Apoptosis is proposed for controlled cell deletion, and
presented morphological evidence distinguishing
apoptosis
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Apoptosis observed by microscopy
Nat Rev Mol Cell Biol 2008, 8:231
Daunorubicin-treated HeLa
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Apoptosis shapes life
Formation of structure
Control of cell numbers
Deletion of structures
Elimination of abnormal cells
. Nat Rev. Mol. Cell Biol. 2002, 3:779
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Why has evolution favored such a system of
self destruction?
Where and when did this system originate?
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The origin of programmed cell death (PCD)
The PCD is not restricted in multicellular organisms
It is found in several unicellular organisms, including
Kinetoplastid parasites: Trypanosoma cruzi and
Trypanosoma brucei
The free-living slime mold Dictyostelium discoideum
The free-living ciliate Tetrahymena thermophila
Yeast
Bacteira: streptomyces
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Programmed cell death in the evolution
Eubacteria
Archaebacteria
Kinetoplastids
Between 1.5 and 2
billion years ago
Slime molds
Red algae
Ciliates
Around 1 billion
years ago
Fungi
Multicellular
animals
Multicellular
plants
0.7 billion years ago
Adapted from Science,1996, 272:1278-1279
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Origin and evolution of PCD
Cell death and differ. 2002, 9:394-404
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Selection for killer genes (encoding toxin) in bacteria for
offensive through evolution
Selection for induction of killer genes in adverse
environmental conditions, providing a selective
advantage to the best-adapted offspring
JC Ameisens hypothesis
PCD and bacterial origin
Selection for genes encoding antidotes for defensive purpose
Multistep theory---
Science 272, 1278
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Since the eukaryote cell is a symbiont that arose
from fusion of different bacteria species,
suggesting that PCD may have evolved from a
resolution of conflict between heterogeneous
genomes within a cell
JC Ameisens hypothesis on PCDs bacterial origin, cont.
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Why has evolution favored such a system of
self destruction?
PCD
For constant selection for the fittest cell in the colony
For optimal adaptation of cell numbers to the environment
For tight regulation of the cell cycle and differentiation
For stable relation between host and parasite
For forming multicellular body from undifferentiated
unicellular cell
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The mitochondrial change during PCD
A striking feature of cells undergoing PCD is that they
suffer alterations in their mitochondrial structure and
function before nuclear structures are affected
The alterations of mitochondria are manifested by
the reduction in the mitochondrial transmembrane
potential (
m
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The reduction of m is likely to be the opening of
mitochondrial permeability transition pores
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Why Is Mitochondrion as the central
control point of apoptosis
Outer membrane
Inner membrane
Matrix
Intermembrane space
Mitochondrial outer
membrane
Mitochondrial inner
membrane
PORIN/VDAC
ANT (adenine nucleotide translocator)
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Endosymbiotic genesis of mitochondria as the
origin of eukaryotic PCD
Theory of JM Frade et al.
In eukaryotic evolution, former invasive bacteria may
have used porin-type channels to enter their host and
to induce its death when the levels of its cytoplasmic
purine nucleotides were dropped
The appearance of adenosine nucleotide translocators in
the primitive eukaryotes, which permitted usage of the
oxidative metabolism of the invaders, provided the basis
for the permeability transition phenomena
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Assignment
Describe at least one example of host and bacteria
invader relationship to support the theory of programmed
cell death derived from Endosymbiotic genesis of
mitochondria proposed by JM Frade et al