The Concepts of Cell Death

Introduction

Our bodies rely on various types of cell death to maintain balance and health. While apoptosis is a controlled process that removes damaged or unnecessary cells, necrosis occurs due to injury or disease, often causing inflammation. Other forms, like autophagy, involve cells self-digesting under stress, and ferroptosis is triggered by iron buildup. Each type of cell death plays a unique role in maintaining health and can influence the development of diseases. In this blog, we'll explore these different forms of cell death and their significance in our bodies.

Cell death, also known as cellular death or cytocide, refers to the process by which a cell undergoes demise. This can occur through various mechanisms. Those mechanisms are as follows.

1.      Apoptosis (programmed cell death).

2.      Necrosis (un-programmed cell death).

3.      Autophagy (self-digestion).

4.      Ferroptosis (iron-dependent cell death).

5.      Pyroptosis (inflammatory cell death).

 

APOPTOSIS

Introduction

The term Apoptosis was coined by John Kerr, Andrew Wylie, and A. R. Currie of the University of Aberdeen, Scotland in 1972.

Apoptosis is programmed and an ordered sequence of events, that leads to the death of the cell.

This process is characterized by the overall shrinkage in volume of the cell and its nucleus, the loss of adhesion to neighboring cells, the formation of blebs at the cell surface, the dissection of the chromatin into small fragments, and the rapid engulfment of the “cadavers” by phagocytosis.

Pathways of Apoptosis

The pathways of apoptosis can be of two types as follows-

Extrinsic Pathway

·     Here, the stimulus for apoptosis is carried by an extracellular messenger protein called tumor necrosis factor (TNF), which was named for its ability to kill tumor cells.

·    TNFs are produced by certain immune cells in response to adverse conditions, such as exposure to ionizing radiation, elevated temperature, viral infection, or toxic chemical agents such as those used in cancer chemotherapy.

·        TNF evokes its response by binding to a trans-membrane receptor, TNFR1 (a death receptor).

·     The cytoplasmic domain of each TNF receptor subunit contains a segment of about 70 amino acids called a “death domain” that mediates protein–protein interactions in response to the binding of the TNF to the receptor.

Mechanism of Extrinsic Pathway

Extracellular signal proteins binding to cell-surface death receptors trigger the extrinsic pathway of apoptosis.

Death receptors are trans-membrane proteins containing an extracellular ligand-binding domain, a single trans-membrane domain, and an intracellular death domain. The receptor includes a receptor for TNF itself and the Fas death receptor. The ligands that activate the death receptors are structurally related to one another and belong to the TNF family of signal proteins.

A well-understood example of how death receptors trigger the extrinsic pathway of apoptosis is the activation of Fas on the surface of a target cell by Fas-ligand on the surface of a killer (cytotoxic) lymphocyte.

When activated by the binding of Fas-ligand, the death domains on the cytosolic tails of the Fas death receptors bind intracellular adaptor proteins, which in turn bind initiator caspases (primarily caspase-8), forming a death-inducing signaling complex (DISC). Once dimerized and activated in the DISC, the initiator caspases cleave their partners and then activate downstream executioner caspases to induce apoptosis.

 

Figure 1: Extrinsic pathway of Apoptosis.

Intrinsic Pathway or Mitochondrial Pathway

·     It is the Apoptotic process triggered by some specialized intracellular proteases, called Caspases (having a cysteine at their active site and cleave their target proteins at specific aspartic acids; they are therefore named so (c for cysteine and asp for aspartic acid).

·      These Caspases are activated in response to internal stimuli, such as irreparable genetic damage, lack of oxygen (hypoxia), extremely high concentrations of cytosolic Ca²⁺, viral infection, ER stress, or severe oxidative stress (i.e., the production of large numbers of destructive free radicals).

·        There are two classes of caspases called as the Initiator caspases and the Executioner caspases.

·        The Initiator Caspases begin the apoptotic process.

·        The major function of the Initiator caspases is to activate the Executioner caspases.

·        One Initiator Caspase Complex can activate many Executioner Caspases.

·        Some examples of the Executioner Caspases are - The Nuclear Lamins (the cleavage of which causes the irreversible breakdown of the nuclear lamina), The DNA Endonucleases (activation of which leads to the précised cleavage of DNA at specific sites, The Cytoskeletons, The Cell-Cell Adhesion Proteins, etc.

Targets of Caspases

·        More than a dozen protein kinases, including focal adhesion kinase (FAK), PKB, PKC, and Raf1.

·        Lamins, which make up the inner lining of the nuclear envelope, resulting the nucleus shrinkage.

·        Proteins of the cytoskeleton, such as those of intermediate filaments, actin, tubulin, and gelsolin.

Mechanism of Intrinsic Pathway

Cells can also activate their apoptosis program from inside the cell, often in response to stresses, such as DNA damage, or in response to developmental signals.

Normally, the Initiator Caspases are present in inactive soluble monomeric forms. In response to an apoptotic signals, they are assembled to a polymeric active complex. Within these complexes, pairs of caspases associate to form dimers, resulting in protease activation.

Each Initiator Caspase in the dimer then cleaves its partner at a specific site in the protease domain, which stabilizes the active complex and is required for the proper function of the enzyme in the cell.

It depends on the release of the mitochondrial proteins into the cytosol, which are normally present inside the inter-membrane space.

A key protein in the intrinsic pathway is cytochrome c, a water-soluble component of the mitochondrial electron-transport chain. It binds to an adaptor protein called Apaf1 (apoptotic protease activating factor-1), causing the Apaf1 to oligomerize into a wheel-like heptamer called an apoptosome.

The Apaf1 proteins in the apoptosome then recruit initiator caspase-9 proteins, which are thought to be activated by proximity in the apoptosome.

The activated caspase-9 molecules then activate downstream executioner caspases to induce apoptosis.

Figure 2: Intrinsic pathway of Apoptosis.

Examples of Apoptosis

·        During embryonic development, the earliest form of the human hand resembles a paddle without any space between the tissues that will become the fingers. The fingers are essentially carved out of the paddle via the elimination of the excess cells by apoptosis.

·        During embryonic development, T lymphocytes are produced that possess receptors capable of binding tightly to proteins present on the surfaces of normal cells within the body. T lymphocytes that have this dangerous capability are eliminated by apoptosis.

·        Apoptosis is involved in the elimination of cells that have sustained irreparable genomic damage that may otherwise lead to cancer.

·        Apoptosis is also responsible for the death of cells that are no longer required, such as activated T cells that have responded to an infectious agent that has been eliminated.

·        Apoptosis appears to be involved in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease.

·        It has been estimated that 10¹⁰ –10¹¹ cells in the adult body die every day by apoptosis.

NECROSIS

Introduction

Necrosis is the death of the cells in your body tissues. Necrosis generally follows some type of physical trauma or biochemical insult.

Necrosis is generally unprogrammed but, like apoptosis, necrosis can also occur as a regulated and programmed process called necroptosis.

Necrosis can occur because of illness, infection, injury, infections, diseases or lack of blood flow to your tissues.

Necrosis is characterized by the swelling of both of the cell and its internal membranous organelles, membrane breakdown, leakage of cell contents into the medium, and the resulting induction of inflammation.

When your body’s cells die of necrosis, they form different patterns and appearances. The dead cells appear one of six ways. These patterns include: 

 1.      Coagulative necrosis: The dead cells remain firm and look normal for days after death. Lack of blood flow or oxygen to any part of your body except your brain can cause coagulative necrosis.

 2.      Liquefactive necrosis: The dead cells partially or completely dissolve within hours of death. Then they transform into a thick, sticky liquid. The cells sometimes appear creamy yellow because pus is forming. Infections and lack of oxygen to your brain can cause liquefactive necrosis.

 3.      Fat necrosis: The damaged cells release enzymes, causing them to turn to liquid. The liquid cells combine with calcium, creating chalky, white deposits on the cells. Acute pancreatitis is the most common cause of fat necrosis. It can also occur in breast tissue.

 4.      Caseous necrosis: The dead cells look white and soft. They’ve been described as looking like cheese — the word caseous means “cheese-like.” Caseous necrosis is uniquely seen in the infectious lung disease tuberculosis.

 5.      Fibrinoid necrosis: The dead cells appear pink and lack structure. This is because plasma proteins (fibrins) are leaking out of your blood vessel walls. Fibrinoid necrosis occurs when an autoimmune disease or infection damage your blood vessels.

 6.      Gangrenous necrosis: The skin appears black and is beginning to rot. Lack of blood flow to your legs can cause gangrenous necrosis. It can sometimes affect your arms and fingers too.

In a nutshell, Necrosis is a type of cell death that occurs due to several external factors like Infection, Trauma like physical injuries, Exposure to Toxins or Radiations, Hypoxia, Inflammation, Gene mutations, Immunological reactions, Nutrient deprivation, Environmental stresses like pH, Temperature, Osmotic stress, etc.

Figure 3: Pathway of Necrosis.

Significances of Necrosis

1. Tissue damage: Necrosis leads to the death of cells and tissues, causing damage to organs and potentially leading to organ failure.

2. Inflammation: Necrosis triggers an inflammatory response, which can cause further damage to surrounding tissues.

3. Disease progression: Necrosis is a hallmark of various diseases, including cancer, cardiovascular disease, neurodegenerative disorders, and infectious diseases.

4. Wound healing: Necrosis can impede the wound healing process by creating a barrier to tissue repair.

5. Immune response: Necrosis can activate the immune system, leading to the production of cytokines and other signaling molecules.

6. Cancer: Necrosis is a characteristic feature of cancer, as tumor cells often undergo necrosis due to rapid growth and insufficient blood supply.

7. Diagnostic marker: Necrosis can serve as a diagnostic marker for certain diseases, such as myocardial infarction (heart attack).

8. Therapeutic target: Necrosis is being explored as a potential therapeutic target for various diseases, including cancer and cardiovascular disease.

 AUTOPHAGY

Introduction

Autophagy refers to the self degradation process, where the cell organelles like mitochondria and other intra-cellular structures are digested proteolytically within lysosomes.

Types of Autophagy

There are three defined types of autophagy: macro-autophagy, micro-autophagy, and chaperone-mediated Autophagy

·        Macro-autophagy delivers cytoplasmic contents to the lysosome through the intermediary of a double membrane-bound vesicle, referred to as an autophagosome, that fuses with the lysosome to form an autolysosome.

·        Micro-Autophagy refers to cytosolic components are directly taken up by the lysosome itself through invagination of the lysosomal membrane.

·        Chaperone-Mediated Autophagy (CMA) is very specific, where targeted proteins are transferred into the lysosome in association with Chaperone Proteins (such as Hsc-70). These chaperon proteins are recognized by the lysosomal membrane receptors called, Lysosomal-Associated Membrane Protein 2A (LAMP-2A), resulting in their unfolding and degradation.

Mechanism of Autophagy

The process begins with the isolation of a small portion of the lipid bilayer from the Endoplasmic reticulum and/or the trans-Golgi (a network of tubules that serves as the major sorting station for proteins and lipids) and Endosome called Phagophore.

This phagophore expands to engulf intracellular cargo like protein aggregates, carbohydrates, lipids, cell organelles, etc. thereby internalizing them.

After internalization, the phagophore degrades those cargos into smaller subunits by the process digestion.

Along with digesting the cargo, it becomes mature by being completely closed, more stable double membrane structure called Autophagosome.

After maturation, the Autophagosome fuses with the Lysosome to form another structure called Autolysosome. The formation of this structure leads to the complete degradation of the cargo.

Lysosomal permeases and transporters export amino acids and other by-products of degradation of the cargo back out to the cytoplasm, where they can be re-used for building macromolecules and for metabolism.

Thus, autophagy may be thought of as a cellular ‘recycling factory’ that also promotes energy efficiency through ATP generation and mediates damage control by removing non-functional proteins and organelles.

Figure 4: Pathway of Autophagy.

Significances of Autophagy

·        Cellular recycling and renovation of organelles, lipids, proteins, etc.

·        Maintains homeostasis in stress conditions like oxidative stress, starvation, or, infection.

·        Protein quality control: Autophagy degrades misfolded or aggregated proteins that may be toxic for the cell.

·        Organelle Maintenance: Autophagy maintains the cell by removing dysfunctional organelles.

·        Immunity: Autophagy is thought to avoid the invading pathogens like Bacteria and Viruses and regulates immune response.

·        Cancer prevention: Autophagy can suppress the tumor growth as it removes damaged cellular components.

·        Metabolic regulation: Autophagy regulates lipid and glucose metabolism.

N.B.- As Autophagy is a cellular process helping the removal of the damaged components of the cell, It does not always lead to the cell death, but sometimes the autophagic activity is out of the control leading to the degradation of the essential cellular components causing cell death. It is also referred to as Type-II Programmed Cell Death.

FERROPTOSIS

Introduction

Ferroptosis is a form of regulated cell death (RCD) that is characterized by the accumulation of toxic lipid reactive oxygen species (ROS) and the execution of a non-apoptotic cell death program.

It is a recently identified form of cell death that is distinct from other forms of RCD, such as apoptosis, necroptosis, and autophagy.

It is triggered by the failure of cellular mechanisms that maintain lipid homeostasis and protect against oxidative damage. This leads to the accumulation of toxic lipid ROS, which ultimately causes cell death.

Figure 5: Pathway of Ferroptosis.

Significance of Ferroptosis

Ferroptosis has been implicated in various diseases, including cancer, neurodegenerative disorders, immunology, toxicology, stem cell biology, and ischemia-reperfusion injury. It is also a target for cancer therapy, as inducing ferroptosis in cancer cells can selectively kill them while sparing healthy cells.

PYROPTOSIS

Introduction

Pyroptosis is a form of programmed cell death (PCD) that is characterized by the activation of inflammatory caspases, particularly caspase-1, and the release of pro-inflammatory cytokines, such as IL-1β and IL-18. It is a distinct form of cell death that is different from apoptosis, necroptosis, and ferroptosis.

Pyroptosis is typically triggered by the detection of pathogens, such as bacteria, viruses, or fungi, by the innate immune system. The activation of pattern recognition receptors (PRRs) leads to the formation of the inflammasome, a multiprotein complex that activates caspase-1 and induces pyroptosis.

Some key features of pyroptosis

1. Inflammatory: Pyroptosis is characterized by the release of pro-inflammatory cytokines and the activation of inflammatory caspases.

2. Caspase-1 dependent: Pyroptosis is dependent on the activation of caspase-1, which is distinct from the caspase-3/7 dependent apoptosis.

3. Non-apoptotic: Pyroptosis is a non-apoptotic form of cell death, meaning that it does not involve the activation of the apoptotic pathway.

4. Lytic: Pyroptosis is a lytic form of cell death, meaning that the cell membrane is disrupted, and the cell contents are released.

 

Figure 6: Pathway of Pyroptosis.

Significances of Pyroptosis

1. Antimicrobial defense: Pyroptosis helps eliminate infected cells and restrict the growth of pathogens, such as bacteria and viruses.

2. Inflammation regulation: Pyroptosis promotes the release of pro-inflammatory molecules, which helps to recruit immune cells to the site of infection.

3. Cancer suppression: Pyroptosis can help eliminate cancer cells and prevent tumor growth.

4. Immune response modulation: Pyroptosis influences the adaptive immune response by releasing cytokines and other signaling molecules.

5. Tissue homeostasis: Pyroptosis helps maintain tissue balance by removing damaged or unwanted cells.

6. Neuroinflammation: Pyroptosis is implicated in neurodegenerative diseases, such as Alzheimer's and Parkinson's, where it contributes to neuronal damage.

7. Autoimmune diseases: Dysregulation of pyroptosis has been linked to autoimmune diseases, like multiple sclerosis and rheumatoid arthritis.

8. Therapeutic target: Pyroptosis is being explored as a potential therapeutic target for various diseases, including cancer, infectious diseases, and autoimmune disorders.

9. Biomarker potential: Pyroptosis-related molecules may serve as biomarkers for disease diagnosis and monitoring.

10. Understanding cell death mechanisms: Studying pyroptosis helps unravel the complexities of cell death pathways and their roles in human health and disease.

 Diseases associated with pyroptosis include:

- Inflammatory bowel disease (IBD)

- Gout

- Atherosclerosis

- Cancer

- Neurodegenerative diseases

 Overall, pyroptosis is an important mechanism of cell death that plays a critical role in the immune response and disease pathogenesis.

 

References:

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