Apoptosis - An Introduction

An Introduction to Apoptosis
By
P B Mallikharjuna PhD
GFGC, Yelahanka, Bangalore
15/06/2021

INTRODUCTION
 The formation of new cells by cell division and in turn the destruction
of old cells by cell death go hand in hand in all multicellular organisms.
 Timely death & discard of old /unwanted /damaged cells is as important
as creation of new cells.(Homeostasis)
Programmed cell death (PCD) is a physiological cell death process
involved in the selective elimination of unwanted cells. (Ellis et al.,1991)
PCD occurs via apoptosis - a Greek word meaning “falling leaves” –
coined by John Kerr et al.,(1972) “Apo- apart ; Ptosis- to drop/ to
fall (Shedding of leaves from trees)
Apoptosis is a form of death that the cell itself initiates, regulates, and
executes using an elaborate arsenal of cellular and molecular machinery.

 This phenomenon came into limelight in 1992 by the understanding the
molecular basis of Apoptosis in Caenorahbditis elegans, a nematode by
Brenner et al (received the 2002 Nobel Prize in Medicine)
 Apoptosis, or programmed cell death, is a highly regulated process that
allows a cell to self-degrade in order for the body to eliminate unwanted or
dysfunctional cells : genetically determined elimination of cells.
 During apoptosis, the genome of the cell will fracture, the cell will shrink
and part of the cell will disintegrate into smaller apoptotic bodies.
 50 to 70 billion cells die each day due to apoptosis in the average human
adult.
 For an average child between the ages of 8 and 14, approximately 20
billion to 30 billion cells die a day

 Why Cells Commit Suicide?
• There seem to be two major reasons. First, apoptosis is one means by
which a developing organism shapes its tissues and organs.
 a human fetus has webbed hands and feet early on its
development. Later, apoptosis removes skin cells, revealing
individual fingers and toes.
 A fetus’s eyelids form an opening by the process of apoptosis.
 During metamorphosis, tadpoles lose their tails through apoptosis.
 In young children, apoptosis is involved in the processes that
literally shape the connections between brain cells,
 in mature females, apoptosis of cells in the uterus causes the
uterine lining to slough off at each menstrual cycle.

Secondly ; Cells may also commit suicide in times of distress, for
the good of the organism as a whole.
 For example, in the case of a viral infection, certain cells of
the immune system, called cytotoxic T lymphocytes, bind to
infected cells and trigger them to undergo apoptosis.
 Also, cells that have suffered damage to their DNA, which
can make them prone to becoming cancerous, are induced to
commit apoptosis.

APOPTOSIS IN ANIMALS
 The process of apoptosis was well studied in animal cells which undergo
orderly series of events both in the nucleus and in the cytoplasm.
 The cells shrink and develop bubble-like protrusions (technical name:
“blebs”) on their surface.
 The DNA in the nucleus gets chopped up into small pieces, and some
organelles of the cell, such as the endoplasmic reticulum, break down
into fragments.
 In the end, the entire cell splits up into small chunks or apoptotic
bodies , each neatly enclosed in a package of membrane.
 These apoptotic bodies release signals that attract debris-eating
(phagocytic) immune cells, such as macrophages (T cells).

 Also, the fragments of the dying cell display a lipid molecule
called phosphatidylserine on their surface. Phosphatidylserine
is usually hidden on the inside of the membrane, and when it is
on the outside, it lets the phagocytes bind and "eat" the cell
fragments

 Apoptosis is mediated by proteolytic enzymes called caspases, which
are synthesized in the precursor form as procaspases.
 When activated by various signals, caspases function to cause cell
death in most organisms, ranging from C. elegans to human beings.
 Caspases are a family of cysteine proteases that cleave at specific
aspartate‐containing sites. They participate in both the initiation of
apoptosis and the disassembly of cellular contents
 More than 10 caspases have been identified. Some of them (e.g.,
caspase 8 and 10) are involved in the initiation of apoptosis, others
(caspase 3, 6, and 7) execute the death order by destroying essential
proteins in the cell.

 The process of apoptosis is highly complex and sophisticated, involving an energy-
dependent series of molecular events.
 Three different pathways work on different mechanisms to achieve apoptosis. All three
pathways converge at the same terminal pathway, which results in the sequential
degradation of cellular organelles.
 1. Extrinsic or death receptor pathway : initiates apoptosis involves transmembrane
receptor-mediated interactions. These interactions take place between ligands and their
corresponding death receptors that are all part of the tumor necrosis factor (TNF) family.
 2. The intrinsic or mitochondrial pathway: initiates apoptosis involves a series of
non-receptor-mediated processes that produce intracellular signals and act directly on
targets within the cell.
 This pathway involves mitochondrial-initiated events.
 The factors that initiate the intrinsic pathway produce intracellular signals that might
act in either a positive or negative fashion.

 3. Perforin/granzyme pathway: is a novel pathway employed by cytotoxic T
lymphocytes that exert their cytotoxic effects on tumor cells and virus-infected
cells. This involves secretion of the transmembrane pore-forming
molecule, perforin, with a subsequent release of cytoplasmic granules through the
pore and towards the target cell.The granules consist of two crucial serine
proteases; granzyme A and granzyme B that activate different proteins in the
pathway.
 4. Execution pathway: Both the extrinsic and intrinsic pathways end at the point
of the execution phase, considered the terminal pathway of apoptosis.This phase of
apoptosis is initiated by the activation of various caspases that activate cytoplasmic
endonucleases and proteases. The cytoplasmic endonucleases degrade the nuclear
material, whereas the proteases degrade the nuclear and cytoskeletal
proteins.Caspase-3 is the most important protein of the executioner caspases and
is activated by any of the initiator caspases (caspase-8, caspase-9, or caspase-10).

APOPTOSIS IN PLANTS
Programmed cell death (PCD)
occurs in many plant cells and
tissues and is involved in
numerous developmental and
adaptive processes, including
gamete formation; embryo
development; degeneration of
tissues in the seed and fruit ;
tissue and organ development (4
through 6); senescence (7); and
responses to environmental
signals and pathogens

The general term for the dissolution of cytoplasm within the cell wall
through the action of the cell’s own catabolic machinery is autolysis.
plants employ different kinds of autolytic process during development
and adaptation.
One way that some plant cells can dispose of their cellular contents is
through autophagy, death process in which the cell “eats itself ” from
within.
Vesicles are produced that engulf portions of the cytosol, including intact
organelles. These vesicles, called autophagosomes, are taken up by
the central vacuole of the cell ,or in some cases fuse with lysosomes
(lytic vesicles), and are broken down by hydrolases.

 Mechanistically, autophagy involves distinctive stages: (i) vesicle
induction; (ii) vesicle expansion; (iii) tonoplast docking and fusion;
and (iv) digestion.
 Molecular components regulating autophagy have been particularly
well described in yeast, but homologs of most of these autophagic
genes (ATG) are also present in Arabidopsis and other plant species.
Tracheid development from a parenchyma cell due to Apoptosis

 Initiation of autophagy is regulated by a target of rapamycin (TOR)
kinase. Under normal conditions TOR kinase phosphorylates ATG1
kinase and accessory proteins, leading to their inactivation. To initiate
autophagy, TOR kinase is inactivated, allowing ATG1 to interact with
several ATG proteins, leading ultimately to the formation of a
vacuolar‐sorting complex that includes a phosphatidylinositol 3‐kinase
(PI3‐K) protein. This is a key vesicle nucleation step in which tubular
pre‐autophagic structures (PASs) are formed, possibly from the
endoplasmic reticulum (ER). PASs coalesce to form a cage that
captures a portion of the cytoplasm.

Apoptosis - An Introduction

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