About 50 to 70 billion cells of our body commit suicide every day.

Although it may seem ironic, cell suicide is a process essential for the healthy survival of every multicellular organism. Cells in multicellular organisms have a built-in, self-destructive system that ensures a timely and/or altruistic death of cells.

Each cell is genetically programmed to commit suicide, at the right time or in response to environmental signals. What triggers these genes, and how do cells commit suicide are two most interesting aspects of a cell, and are especially important as far as cancers and degenerative disorders are concerned.

The cell death that occurs through the activation of such intrinsic self-destructive mode is termed as programmed cell death and encompasses a series of well-defined biochemical events. Cell suicide is a vital event during several embryonic or early developmental stages in almost all multicellular organisms. A cell may also commit suicide if it gets internally damaged beyond repair or infected, as well as if it has grown old or accomplished the desired role and is no longer required.

A process called apoptosis is the most widely studied and characterized cell death mechanism, and is often used synonymously with 'cell suicide' and 'programmed cell death.' Let us understand how do cells commit suicide through apoptosis, and what are the lesser studied and debated non-apoptotic ways in which a cell may initiate death.

Apoptosis ― Death by Design

Apoptosis or type I cell death is the major type of PCD through which cell suicide occurs, and is characterized by a distinct set of cellular morphology. The cell shrinks, its contents are degraded, DNA is defragmented, and the entire cell is broken down into pieces or blebs, which are then engulfed by phagocytic cells.

This self-killing mechanism of cells was first described by Carl Vogt in 1842, but was referred to as apoptosis by scientists Kerr J.F., Wyllie A.H., and Currie A.R., in 1972. The active players in apoptosis are enzymes known as caspases or killer proteases, which get activated owing to certain molecular triggers and orchestrate the further events.

The Chase Begins

Induction of apoptosis
Induction of Apoptosis

Apoptosis is triggered through two ways:
  • Intrinsic (Mitochondrial) Pathway: Under normal conditions, cells are prevented from undergoing apoptosis by a set of anti-apoptotic proteins belonging to the Bcl-2 family of proteins present in the mitochondrial membrane. The absence of growth factors, DNA damage, cellular damage, or other cellular stress alters the activity of these proteins. As a result, mitochondrial membrane permeability is affected, and a molecule called cytochrome c is released into the cytoplasm. This molecule activates the initiator caspases, thus, triggering apoptosis.
  • Extrinsic (Receptor-mediated) Pathway: This pathway for inducing apoptosis depends on certain death receptors that are present on the cellular surface, and hence, it is also known as the death receptor pathway. These receptor molecules are transmembrane proteins, and the part which extends in the cytoplasm of the cell has a unique domain called the death domain. Each receptor can interact with a unique signaling molecule termed ligand. The most studied receptor-ligand pair is that of Fas receptor (FasR) and Fas ligand (FasL). Once the death receptor of the cell is bound by its cognate ligand, it recruits intracellular messenger proteins near the death domain. In case of Fas-FasL interaction, FADD (Fas-associated Death Domain) protein is recruited, which binds to the death domain receptor. This recruits and activates the initiator caspases, which can then initiate cellular destruction.
Caspases ― Licensed to Kill

Morphological changes during apoptosis
Morphological Changes During Apoptosis

Caspases (cysteine-dependent aspartate-directed proteases) are a set of proteases that specifically cut proteins at the site containing the amino acid called aspartic acid. Caspases are classified into initiator and effector caspases that are present in an inactive state in the cell.

The above-mentioned pathways lead to the activation of initiator caspases, which in turn, chop off a fragment of effector caspases, thereby, activating them. The effector caspases bring about the mass breakdown of proteins present in the cell, as well as activate nucleases. This leads to:
  • Chromatin condensation
  • DNA fragmentation
  • Nuclear disintegration
  • Membrane blebbing
The broken fragments of cells, organelles, and nucleus are neatly packaged into vesicles termed as apoptotic bodies. The apoptotic bodies contain certain molecules on their surface, which indicate their identity to the normal phagocytic cells present nearby. These phagocytic cells engulf the apoptotic bodies, degrade them through their lysosomal machinery, and utilize the resultant amino acids, sugars, and nucleotides for their own metabolic activities.

Autophagic Cell Death (ACD) ― Partner in Crime

Autophagy is the process used by cells to recycle its long-lived as well as damaged proteins and organelles, and is considered to be a survival strategy of cells. Autophagy occurs through the trapping of target components into a vesicle called autophagosome. This vesicle fuses with the lysosome and is degraded by the lysosomal enzymes, releasing the building blocks into the cytosol.

Dying cells have often being observed to contain a large number of autophagosomes, suggesting a non-apoptotic cell death mechanism termed as autophagic cell death (ACD) or type I cell death. Genetic studies have revealed that the absence of autophagy-related genes hinders the process of apoptosis.

However, it is still a topic of debate whether formation of large number of autophagosomes is induced to achieve cell death or is it a consequence of cell death. It has been suggested that these autophagosomes might serve as a 'clearing mechanism' for the neat disposal and recycling of the components of a dying cell. Its precise role as a cell death initiator remains to be confirmed.

Necrosis ― Suicide or Murder?

Necrosis or cell death type III refers to cell death that occurs due to extrinsic factors, like injury, infections, toxins etc. It is characterized by biochemical events distinct from those observed in apoptosis and autophagy. The organelles swell up, cell volume increases, and the cell membrane ruptures releasing cytoplasmic contents. This leads to the activation of immune cells, and is generally followed by an inflammatory response.

It has traditionally been acknowledged as an unplanned, accidental death, and is considered to be a passive process. However, recent studies indicate the involvement of cellular signaling molecules and catabolic pathways in the initiation of necrosis. This mode of programmed necrosis has been termed as necroptosis (necrosis + apoptosis), and it is known to function in conditions where apoptosis cannot be triggered.

Cell Suicide in Plants

PCD is more widely studied and characterized in animals, and the knowledge regarding plant cell suicide is comparatively limited. Although it is known that a complex network for PCD exists in plants, there are neither defined markers of cell death nor analogous destructive proteins, like caspases. Chloroplasts and vacuoles are the key organelles involved in the PCD process. The cell wall remains intact in the dying plant cells. Moreover, plants lack phagocytic cells that can degrade the debris generated from dying cells. The precise cellular mechanisms of plant PCD are still being investigated.

Food for Thought
If each cell has a genetic program that initiates self-destruction, then cancer cells have it too. Either they have managed to devise a way to overcome it, or have introduced flaws in them. Can we somehow fix the pathway, or trigger it to bring about the demise of cancer cells? Moreover, if we are able to learn how they do it, can we prevent aging?

The howdunit of cell suicide does not end here, and new molecules, especially proteins, that serve as messengers of death are being identified and studied. The precise understanding as to how and why cells commit suicide presents a huge challenge to the scientific community, and investigations regarding the same reveal new aspects about this magnificent marvel named cell.