Apoptosis

Programmed cell death through apoptosis

Apoptosis occurs from early development through adulthood – whenever the cells of the organism need to be removed to enable the health or function of the organism.

Examples of apoptosis at work during fetal development include the elimination of extra tissue between developing fingers and toes as well as shaping organs as diverse as the heart and inner ear by removal of cells that are no longer necessary. Importantly, the removal of cells must be accomplished in a controlled manner.

In addition to shaping limbs and organs, programmed cell death (PCD) plays a crucial role in the nervous system. During this process, apoptosis removes excess neurons to refine synaptic connections and establish functional neural circuits. In embryogenesis, it helps maintain tissue integrity by eliminating cells that fail to integrate properly or carry potentially harmful mutations. These tightly regulated events are essential for preventing developmental abnormalities and are controlled by signaling pathways involving caspase activation and pro-apoptotic factors.

After birth, apoptosis continues to play a critical role in maintaining cellular homeostasis through cell turnover. This is necessary for clearing unrepairable damaged cells, such as in the removal of lung epithelial cells after pneumoniae infection. Apoptosis also plays important roles in immunity such as in the removal of certain immune cells to establish immune tolerance.

Differentiating apoptosis from necrosis

Apoptosis and necrosis both lead to cell death but occur through distinct mechanisms. The process of apoptosis results in controlled, programmed cell shrinkage and nuclear fragmentation via the action of proteolytic enzymes called caspases, as well as an anti-inflammatory cytokine release. The result is an ordered, intentional cell death usually in response to tightly regulated signals.

In contrast, necrosis leads to accidental, uncontrolled cell death characterized by cell swelling, lysis and a pro-inflammatory cytokine release. It is often the result of an extreme external factor such as injury.

Autophagy is sometimes included as a third form of cell death. Like apoptosis, autophagy is a controlled process, in this case employing lysosomes to ingest and break down cellular organelles. While it can lead to cell death, autophagy more generally provides a mechanism for recycling cellular materials.

How does apoptosis work?

Cellular apoptosis can be triggered by a variety of internal and external stimuli that activate caspase enzymes within the cell. Once activated, the caspases break the cell down into fragments that are then consumed and cleared from the body by phagocytes. This process includes the breakdown of the plasma membrane, initially visible as membrane blebbing.

Apoptosis can occur through several major pathways, depending on the origin of the signal. These include:

• Intrinsic apoptosis, triggered by signals from within the cell, such as internal stress or DNA damage.
• Extrinsic apoptosis, initiated by external signals that bind to specific receptors on the cell surface. Death receptor signaling is the classic example of extrinsic apoptosis.
• Granzyme-mediated apoptosis, including Granzyme A and Granzyme B, which is used by immune cells to eliminate infected or abnormal cells.

Key cellular changes during apoptosis

Apoptotic cells display key morphological changes including chromatin condensation, nuclear fragmentation, membrane blebbing, and ultimately the formation of apoptotic bodies. These are quickly engulfed by macrophages or neighboring cells, preventing inflammation – a hallmark that distinguishes apoptosis from necrosis.

Consequences of dysregulated apoptosis

Apoptosis of cells is tightly regulated, with too much or too little apoptosis associated with human disease. (1) For example, disruptions that prevent cellular apoptosis allow cells to live longer than they should, increasing the possibility of developing cancer, inflammatory disease or viral infection.

Conversely, overactive apoptosis results in the death of cells that are not actually supposed to die and can lead to neurodegenerative diseases such as Alzheimer's and Parkinson's, hematologic disorders such as the loss of CD4+ lymphocytes in HIV positive patients (2) and tissue damage.

Apoptosis and cancer – understanding the connection

Cell apoptosis is critical for prevention of cancer due to its role in removal of abnormal cells that have acquired genetic mutations or sustained damage that could lead to uncontrolled growth. When apoptosis is disrupted, tumor formation and malignancy are free to proceed.

It is therefore not surprising that cancers are often found to harbor mutations in genes involved in apoptosis signaling pathways. Genes like TP53, which encodes a protein critical for initiating apoptosis in response to DNA damage. When p53 is compromised, damaged and potentially cancerous cells can survive and propagate. For this reason, activating pro-apoptotic proteins or inhibiting anti-apoptotic proteins is an important focus of cancer therapies (3).

References

1. Elmore S. Apoptosis: A review of programmed cell death. Toxicol Pathol. 2007;35(4):495–516.
2. Ekabe CJ, Clinton NA, Agyei EK, Kehbila J. Role of apoptosis in HIV pathogenesis. Adv Virol. 2022;2022:8148119.
3. Pistritto G, Trisciuoglio D, Ceci C, Garufi A, D’Orazi G. Apoptosis as anticancer mechanism: Function and dysfunction of its modulators and targeted therapeutic strategies. Aging (Albany NY). 2016;8(4):603–19.