Apoptosis: Organised Cell Death

Sometimes, as a highly complex and intricate organism, your body needs to kill your own cells. Wait, what? 

Hold on, let me explain. There are 2 main kinds of cell death: apoptosis and necrosis. Apoptosis is the controlled and tidy removal of cells, also known as organized cell death. 

 Apoptosis:  a series of molecular steps that lead to organized cell death. 

There are 3 main purposes of apoptosis:

1. To remove damaged or defective cells (cancerous or infected)

2. To remove old cells 

3. For fetal development in the womb: apoptosis sculpts the body from tissue. For instance, apoptosis removes the webbing between fingers and eyelid cracks.

So how is apoptosis important in our daily lives? For one instance, apoptosis greatly reduces your passive risk of developing malignant tumors. Typically, your body suppresses tumors before they can properly form by taking preventative measures such as removing cells that are at risk of mutating, have already mutated (genetic damage), are too old, or simply aren’t needed anymore. 

• Fun Fact: according to Bionity.com, 50 billion to 70 billion cells die each day due to apoptosis in the average human adult, while approximately 20 billion to 30 billion cells die in the average child aged 8 to 14.

Necrosis

Necrosis: unregulated, uncontrolled (messy), cell death; cells dying unexpectedly by some accident or injury

Unlike apoptosis, necrosis is the opposite of the controlled and tidy removal of cells. When cells die by necrosis, they die messily, spilling their internal organelles into their surroundings. This causes inflammation and triggers an immune response, often damaging neighboring cells.

This occurs when a cell has been heavily damaged, typically through external forces such as oxygen deprivation, physical injuries, or viruses.

Fig 1: the effects of apoptosis compared to necrosis.

Initiation: Intrinsic (Mitochondrial) Pathway

There are 2 main pathways on how apoptosis is triggered:

1. Intrinsic (mitochondrial) pathway

2. Extrinsic (death ligand) pathway 

Handy Definitions:

Mitochondrial pathway: the pathway of apoptosis which is initiated by the detection of internal cellular damage. Also known as the intrinsic pathway. 

Caspase enzymes: catalysts that cleave specific intracellular proteins during apoptosis 

The intrinsic pathway involves the mitochondrial membrane either being damaged or changing permeability and releasing an enzyme called cytochrome C, which is toxic to the cell.

Fun Fact: the membranes of organelles inside your cells are crucial for maintaining separate internal environments. For instance, Cytochrome C is crucial for ATP synthesis inside the mitochondria, but ‘toxic’ when released into the cell’s cytosol.

The mitochondrial pathway occurs when a cell experiences severe internal stresses. This encompasses DNA damage, mechanical injury, pathogens, toxic compounds in the environment, or naturally occurring agents that damage cells such as ultraviolet light and nutrient or oxygen deprivation.

STEPS:  

1. The mitochondria leak their internal components, releasing cytochrome C into the cytosol.

2. Cytochrome C bonds with Apaf1.

3. Apaf1  bonds with procaspase 9, cutting off its top and forming caspase 9.

4. Caspase 9 creates procaspase 3, which splits to become caspase 3.

5. Caspase 3 then cuts the cell’s cytoskeleton.

Fig 2: a diagram of the enzymes involved in the mitochondrial pathway.

Initiation: Extrinsic (Death Ligand) Pathway

Handy Definitions:

Ligand: a molecule that binds to another molecule called a receptor to send signals within or between cells

NKT cell:  (natural killer T-cell) An immune cell. Identifies that a cell has changed, and needs to die, and releases signaling molecules, Fas-L (death ligand)

As the name suggests, the extrinsic pathway is initiated by an extracellular source, and makes use of molecules on the surface of the plasma membrane which can be used to ‘communicate’ between cells. In the following example, the extracellular source is a death ligand from a white blood cell.

Steps of the Extrinsic Pathway

1. An NKT cell finds an abnormal cell, and orders apoptosis by releasing the death-signaling molecule, Fas-L.

2. Fas-L binds to the receptor Fas-R, on the surface of the cell membrane. This attracts 2 more Fas-R molecules, resulting in 3 receptors attached to the ligand, creating a second shape.

   1. → the receptors are able to move across the cell membrane because of the fluid mosaic model, which states that the plasma membrane acts like a fluid (think of the receptors as toy boats in a bath).

3. The new shape attracts 2 FADD molecules which bind to the 3 Fas-R, creating a third shape.

4. This then attracts the molecule procaspase 8,  and the top of the procaspase is CUT OFF, which becomes the enzyme caspase 8.

5. The separated enzyme caspase 8 attaches to procaspase 3, and the top is cut and turned into enzyme caspase 3.

6. Finally, caspase 3 cuts the cell’s cytoskeleton, starting the cell’s deterioration.

   
   

 💡 TIP:  Fas-L and Fas-R stand for LIGAND and RECEPTOR.

 💡 TIP: Proteins or enzymes are ‘activated’ when they bind to molecules.

KEY IDEA: Molecules interact because of COMPLEMENTARY SHAPES and CHARGES.

You can see how the initiation of apoptosis is actually one large chain reaction. One molecule binds and changes shape, which binds to another and changes shape, and the cycle repeats until the end result synthesizes a molecule with a specific function.

Fig 3: a diagram depicting the enzymes involved in the extrinsic (left) and intrinsic (right) pathways of apoptosis. (Bhosale P B, et al., 2020).

Caspase 3 is an essential enzyme for apoptosis. Notice how despite the different initial enzymes, both the intrinsic and extrinsic pathways result in caspase 3 being synthesized and cleaving the cytoskeleton. 

Execution

Okay, that was a lot of protein reactions and specific molecule names. But luckily, we’re getting to the (more) interesting part. We know what apoptosis is, when it occurs, and how it starts. But how exactly does it kill a cell in an organized and tidy manner?

A cell’s cytoskeleton is its structural support. When caspase 3 severs the cytoskeleton filaments the cell collapses inwards, characterizing the next part of apoptosis.

1. Cell shrinkage.

As the cytoskeleton is cut, the cell starts to collapse as the membrane bulges outward without support in a process known as blebbing, bubbles (known as blebs) form on the cell’s surface. The organelles disintegrate as chromosomes of the DNA condense and the nuclear membrane starts to break down.  

1. Formation of apoptotic vesicles.

The bubbles on the surface of the cell membrane break away from the cell, becoming known as apoptotic bodies, and carrying away parts of the cell’s contents. Inside the cell, the nucleus and chromatin fragments are cut into smaller pieces that are eventually carried away by the apoptotic bodies.

2. Apoptotic bodies disperse

Eventually, the cell is broken down into several apoptotic bodies. Large white blood cells called phagocytes engulf the apoptotic bodies through a process known as phagocytosis and break them down into harmless soluble material using digestive enzymes from lysosomes.

Fig 4: an annotated diagram of apoptosis.

Apoptotic bodies:  A bleb, once it has broken away from the cell.

Phagocyte: A type of immune cell specialized for engulfing and breaking down foreign matter or dead cells.

Fun Fact: many viruses alter a cell’s DNA to remove their death receptors, allowing infected cells to hide from your immune system for longer.

Application Exploration:

Apoptosis and Cancer Minor genetic mutations happen more frequently than we may realize! However, our body keeps it under control through rapid detection and removal through apoptosis. These mutations only become known as ‘cancer’ once they become too much for our cells and immune system to handle, and grow into malignant tumors.

How Mutated Cells Escape Apoptosis - P53

Hold on, if our body kills mutated cells, how do cancer cells escape death? Sometimes, not enough cytochrome C is released from mitochondria, or not enough death receptors are activated, and too little caspase 3 enzymes are synthesized to properly destroy the cytoskeleton, resulting in apoptosis failing and the mutated cell surviving. 

Let’s look at a specific example: If you think back to the extrinsic pathway, apoptosis is initiated by an NKT cell releasing a signaling molecule called a death ligand, which tells a cell to kill itself. 

In a cell’s DNA, they have a P53 gene that codes for the protein P53, which is a key part of building the receptors (named DR4 and DR5) on the cell’s membrane that responds to a specific death ligand called T.R.A.I.L. But in some cancerous cells with a P53 gene mutation, the changed genes produce differently shaped P53 proteins,  resulting in the death receptors being formed incorrectly and being unable to bind to T.R.A.I.L. Thus, the mutated cell does not respond to the apoptosis order and develops into a tumor.

For an analogy, think of the receptors as a mailbox, and the death ligand as a letter. The mutated cell removes their ‘mailbox’, preventing themselves from receiving as many ‘letters’, and thus being unable to receive any instructions.

T.R.A.I.L: A death ligand.

• Tumour-necrosis-factor Related Apoptosis Inducing Ligand. 

• Can be released by neighboring cells

Conclusion

Okay, that was a huge amount of information, but we got through it all.

Human anatomy is an incredibly complex system, made up of countless tiny units all working together to function cohesively. When damaged, your cells risk mutating into cancer, so your body removes them through apoptosis to prevent possible tumors. 

Apoptosis is just one of the many complex and beautiful systems the human body has in place to regulate your cells and keep homeostasis. So don’t forget to give a bit of appreciation for the wonderful and intricate processes that keep you alive and functioning.

Works Cited

“Apoptosis.” Bionity.com, 2025, www.bionity.com/en/encyclopedia/Apoptosis.html. Accessed 1 Apr. 2025.

Bhosale P B, et al. Flavonoid-induced apoptotic cell death in human cancer cells and its mechanisms. Journal of Biomedical and Translational Research. 2020, 21(2): 50-58.

“Cell Death by Apoptosis.” Creative-Diagnostics.com, 21 Sept. 2023, www.creative-diagnostics.com/cell-death-by-apoptosis.htm. Accessed 31 Mar. 2025.

Cleveland Clinic. “Cell Death: Types, Causes & Necrosis.” Cleveland Clinic, 28 Sep. 2023, my.clevelandclinic.org/health/articles/cell-death.

Clinic, Cleveland. “Cell Death: Causes, Apoptosis, Autophagy & Necrosis.” Cleveland Clinic, 5 Oct. 2023, my.clevelandclinic.org/health/articles/cell-death. Accessed 31 Mar. 2025.

Gentry, Katherine, et al. Edrolo VCE Biology. Units 1 & 2. Fitzroy, Vic., Edrolo, 2021.

Helmenstine, Anne. “Apoptosis - Definition and Importance.” Science Notes and Projects, 20 Mar. 2024, sciencenotes.org/apoptosis-definition-and-importance/.

National Cancer Institute. “NCI Dictionary of Cancer Terms.” National Cancer Institute, Cancer.gov, 2019, www.cancer.gov/publications/dictionaries/cancer-terms/def/apoptosis.

Stiban, Johnny. “Regulation of Ceramide Channel Formation and Disassembly: Insights on the Initiation of 

Apoptosis.” ResearchGate, 2015, www.researchgate.net/figure/Cytology-of-apoptosis-The-different-stages-of-apoptotic-cell-death-start-by-cellular_fig3_274013152.