Apoptosis or Programmed Cell Death

 

Apoptosis or Programmed Cell Death

Apoptosis is a process that occurs in multicellular organism when a cell intentionally “decides” to die. This often occurs for the greater good of the whole organism, such as when the cell’s DNA has become damaged and it may become cancerous.

Apoptosis is referred to as “programmed” cell death because it happens due to biochemical instructions in the cell’s DNA; this is opposed to the process of “necrosis,” when a cell dies due to outside trauma or nutrient deprivation.

Like many other complex cellular processes, apoptosis is triggered by signal molecules that tell the cell it’s time to commit cellular “suicide.”

The two major types of apoptosis pathways are “intrinsic pathway,” where a cell receives a signal to destroy itself from one of its own genes or proteins due to detection of DNA damage; and “extrinsic pathway,” where a cell receives a signal to start apoptosis from other cells in the organism. The extrinsic pathway may be triggered when the organism recognizes that a cell has outlived its usefulness or is no longer a good investment for the organism to support.

Apoptosis plays a role in causing and preventing some important medical processes. In humans, apoptosis plays a major role in preventing cancer by causing cells with damaged DNA to commit “suicide” before they can become cancerous. It also plays a role in the atrophy of muscles, where the body decides that it’s no longer a good idea to spend calories on maintaining muscle cells if the cells are not being regularly used.

Apoptosis destroys pre-cancerous cells and cells that are no longer useful to the organism. Because apoptosis can prevent cancer, and because problems with apoptosis can lead to some diseases, apoptosis has been studied intensely by scientists since the 1990s.

Apoptosis is required for Embryogenesis, Metamorphosis, Endocrine dependent tissue atrophy, Normal tissue turnover, Variety of pathologic conditions, etc.

Necrosis Vs Apoptosis

Cells that die as a result of acute injury typically swell and burst. They spill their contents all over their neighbors—a process called cell necrosis—causing a potentially damaging inflammatory response. By contrast, a cell that undergoes apoptosis dies neatly, without damaging its neighbors. The cell shrinks and condenses. The cytoskeleton collapses, the nuclear envelope disassembles, and the nuclear DNA breaks up into fragments. Most importantly, the cell surface is altered, displaying properties that cause the dying cell to be rapidly phagocytosed, either by a neighboring cell or by a macrophage before any leakage of its contents occurs. This not only avoids the damaging consequences of cell necrosis but also allows the organic components of the dead cell to be recycled by the cell that ingests it.

The intracellular machinery responsible for apoptosis depends on a family of proteases that have a cysteine at their active site and cleave their target proteins at specific aspartic acids. They are therefore called caspases (cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases). 

Apoptopic caspases are subcategorised as:

Initiator Caspases (Caspase 2, Caspase 8, Caspase 9, Caspase 10)

Executioner Caspases (Caspase 3, Caspase 6 and Caspase 7)

Caspases are synthesized in the cell as inactive precursors, or procaspases, which are usually activated by cleavage at aspartic acids by other caspases. Once activated, caspases cleave, and thereby activate, other procaspases, resulting in an amplifying proteolytic cascade.

Initiator caspases auto-proteolytically undergo cleaving and activation.  Executioner caspases are cleaved by initiator caspases. Once initiator caspases are activated, they produce a chain reaction, activating several other executioner caspases. Executioner caspases degrade over 600 cellular components and induce the morphological changes for apoptosis.

For example, some of the activated caspases then cleave other key proteins in the cell. Some cleave the nuclear lamins, for example, causing the irreversible breakdown of the nuclear lamina; another cleaves a protein that normally holds a DNA-degrading enzyme (a DNAse) in an inactive form, freeing the DNAse to cut up the DNA in the cell nucleus. In this way, the cell dismantles itself quickly and neatly, and its corpse is rapidly taken up and digested by another cell.

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 Activation of the intracellular cell death pathway, like entry into a new stage of the cell cycle, is usually triggered in a complete, all-or-none fashion. The protease cascade is not only destructive and self-amplifying but also irreversible, so that once a cell reaches a critical point along the path to destruction, it cannot turn back.

Major cytological changes of apoptosis:

·                  Cell shrinks

·                  Cell fragments

·                  Cytoskeleton collapses

·                  Nuclear envelope disassembles

·                  Cells release apoptotic bodies

·                  The membrane enclosed cell fragments are phagocytosed by macrophages and other cells.

Apoptosis Pathway

There are two major types of apoptosis pathways, extrinsic and intrinsic.

The extrinsic pathway of apoptosis begins outside a cell, when conditions in the extracellular environment determine that a cell must die. The intrinsic pathway of apoptosis pathway happens when injury occurs within the cell and the resulting stress activates the apoptotic pathway.  In both the intrinsic and extrinsic pathway of apoptosis, signaling results in the activation caspases, that act in a proteolytic cascade for apoptosis.

Extrinsic Pathway or death-receptor pathway

This is initiated by the activation of death receptors on the cell surface. Killer lymphocytes for example, can induce apoptosis by producing a protein called Fas ligand, which binds to the death receptor protein Fas on the surface of the target cell. This activates the death domains at the cytoplasmic tail of the receptor. The adaptor protein FADD will recruit pro-Caspase 8 via the DED domain. This FasR, FADD and pro-Caspase 8 form the Death Inducing Signaling Complex (DISC) and Caspase-8 is activated. This either lead to downstream activation of the intrinsic pathway by inducing mitochondrial stress, or lead to direct activation of Executioner Caspases and apoptosis.

Intrinsic Pathway or mitochondrial pathway

Intrinsic stresses such as arising from oncogenes, direct DNA damage, hypoxia, survival factor deprivation, etc can activate the intrinsic apoptotic pathway. p53 is a sensor of cellular stress and is a critical activator of the intrinsic pathway.  p53 initiates apoptosis by the transcriptional activation of pro-apoptotic Bcl2 family members and inhibiting anti-apoptotic Bcl2 proteins.  p53 also activates other genes contributing to apoptosis and genes that lead to increases in Reactive Oxygen Species.  These ROS lead to oxidative damage to mitochondria.

Mitochondria are induced to release the electron carrier protein cytochrome c into the cytosol.  This molecule binds an adaptor protein (APAF-1), which recruits initiator Caspase-9. This leads to the formation of a Caspase activating multiprotein complex called the Apoptosome. Once activated, Caspase 9 will cleave and activate other executioner caspases and leads to degradation of cellular components for apoptosis.

The apoptosome is a large quaternary protein structure formed in the process of apoptosis. It is a multimolecular holoenzyme complex assembled around the adaptor protein Apaf1. Its formation is triggered by the release of cytochrome c from the mitochondria.  The apoptosome triggers the activation of caspases in the intrinsic pathway of apoptosis. Once activated, this initiator caspase can then activate effector caspases and trigger a cascade of events leading to apoptosis.

The external stimuli activate death receptors in extrinsic pathway resulting in the formation of activated caspase 8 which either activate intrinsic pathway by inducing mitochondrial stress or activate executioner caspases for apoptosis.  In intrinsic pathway, the cyctochrome c release results in the activation of caspase 9 which further activates executioner caspases for apoptosis.  Executioner caspases such as caspase 3, 6 and 7 degrade over 600 cellular components and mediates apoptosis. Executioner caspases in apoptosis are termed so because they coordinate the destruction of cellular structures such as DNA fragmentation or degradation of cytoskeletal proteins.

When Does Apoptosis Occur?

Apoptosis occurs when a cell’s existence is no longer useful to the organism. This can occur for a few reasons.

If a cell has become badly stressed or damaged, it may commit apoptosis to prevent itself from becoming dangerous to the organism as a whole. Cells with DNA damage, for example, may become cancerous, so it is better for them to commit apoptosis before that can happen.

Other cellular stresses, such as oxygen deprivation, can also cause a cell to “decide” that it is dangerous or costly to the host. Cells that can’t function properly may initiate apoptosis, just like cells that have experienced DNA damage.

In a third scenario, cells may commit apoptosis because the organism doesn’t need them anymore due to its natural development.

One famous example is that of the tadpole, whose gill, fin, and tail cells commit apoptosis as the tadpole metamorphoses into a frog. These structures are needed when the tadpole lives in water – but become costly and harmful when it moves onto dry land.