Prof C Gourlay - Introduction to Apoptosis (3) Frontiers for cell biology

Introduction

Topic: Apoptosis

Course: BIOS5030 - An Introduction to Apoptosis by Prof. Campbell Gourlay

Text Reference: Chapter 18 - Molecular Biology of the Cell (Alberts)

Defining Apoptosis

• Origin of the term: Greek "apo" (from) + "ptosis" (falling), indicating a process of falling away or removal.

• First documented usage in 1972 by Andrew H. Wyllie and John Kerr, who established the term's significance in cellular biology.

• Historical references:

  • Hippocrates described it as the "falling off of the bones", suggesting an understanding of natural decay.

  • Galen referred to it as the "dropping of the scabs", illustrating an early observation of tissue loss.

Major Differences in Cell Death Mechanisms

Ordinary Cell Death vs. Acute Injury Death

• Necrosis: A pathological form of cell death characterized by:

  • Cell swelling, leading to rupture and the spilling of cellular contents into the extracellular space.

  • Subsequent recruitment of immune cells and triggers an inflammatory response, which can result in further tissue damage and scarring.

• Apoptosis: A highly regulated and intentional process that involves:

  • Cells shrink or condense, a hallmark of apoptotic changes, preventing damage to neighboring cells.

  • Consumption of apoptotic bodies by neighboring cells via phagocytosis, effectively removing dying cells without triggering inflammation.

Comparing Apoptosis and Necrosis

Necrosis

• Causes: Often triggered by external factors such as physical trauma, chemical agents, or attacks by cytotoxic T cells.

• Symptoms: Includes swelling, loss of membrane integrity, bursting of cells, and an inflammatory response that can lead to pain and further tissue damage.

Apoptosis

• Characteristics: A programmed and orderly process involving a cascade of molecular signals that promote cellular dismantling.

• Symptoms: Characterized by cell shrinkage, nuclear fragmentation, chromatin condensation, and the formation of apoptotic bodies that are cleared away without causing inflammation.

Importance of Apoptosis

• Essential for maintaining cellular and tissue homeostasis, ensuring proper functioning of biological systems.

• Dysregulation can lead to severe consequences:

  • Insufficient apoptosis may contribute to cancer development, as cells that should undergo programmed death continue to proliferate.

  • Excessive apoptosis can lead to degenerative diseases and tissue loss.

• Statistical context: Approximately 50-70 billion cells die daily due to the regulated process of apoptosis in an average adult, highlighting its significance in overall health.

Stimuli Causing Apoptosis

• Various stimuli can trigger apoptosis, including:

  • Withdrawal of growth factors necessary for cell survival.

  • DNA damage from environmental factors like UV radiation, leading to potential carcinogenic effects if unrepaired.

  • Cytoskeletal damage, often induced by chemotherapeutic agents targeting cancer cells.

  • Endoplasmic reticulum dysfunction, which can disrupt protein folding and lead to cellular stress.

  • Heat/cold shock, which creates stress conditions that lead to apoptosis.

  • Oxidative stress, resulting from excess reactive oxygen species that cause damage to cellular components.

  • Removal of non-adherent cells (Anoikis), essential in preventing detached cells like cancer cells from surviving.

  • Immune response triggers, particularly from cytotoxic lymphocytes targeting infected or cancerous cells.

  • Ischemic conditions post heart attack or stroke, where the lack of blood flow leads to cellular damage and apoptosis.

Developmental Role of Apoptosis

• Apoptosis plays a crucial role in developmental processes:

  • Integral in metamorphosis, such as the transition from tadpole to frog, where specific cells must be eliminated for proper development.

  • Essential for the formation and remodeling of tissues and organs, particularly during embryogenesis.

  • Regulated apoptosis is crucial for normal nervous system development, enabling proper neuronal connections and eliminating surplus neurons.

Genetic Control of Apoptosis in C. elegans

• Ced (Cell death) Genes:

  • A set of genes responsible for programmed cell death during the development of C. elegans, a model organism in apoptosis research.

  • 131 specific cells are known to undergo apoptosis during development, illustrating the precision of this process.

• Key genes and their roles:

  • ced-3: A crucial gene responsible for initiating apoptosis, encoding caspase proteins that execute cell death.

  • ced-4: Works in conjunction with ced-3 to promote apoptosis.

  • ced-9: Functions as an anti-apoptotic factor, regulating the activity of ced-3 and ced-4.

Caspases in Apoptosis

• Caspases: Cysteine proteases that play a central role in mediating apoptosis.

  • Divided into two classes: initiator caspases, which trigger the apoptotic cascade, and executioner caspases, which carry out the death program.

  • The activation of initiator caspases leads to a cascade of signal amplification, facilitating the rapid progress of apoptosis.

Mechanism of Apoptosis

• Key cellular changes that occur during apoptosis include:

  • Membrane blebbing, where cellular protrusions form and ultimately detach.

  • Nuclear fragmentation, where the genetic material is degraded.

  • Chromatin condensation, contributing to the formation of distinct apoptotic bodies.

  • The formation of apoptotic bodies that are swiftly engulfed via phagocytosis, preventing inflammation and surrounding tissue damage.

Pathways of Apoptosis

Two Main Pathways:

1. Intrinsic Pathway:

   • Initiated by internal cellular stresses, such as DNA damage or mitochondrial dysfunction.

   • Involves the Bcl-2 protein family, which regulates the release of pro-apoptotic factors from mitochondria.

   • Activation leads to mitochondrial outer membrane permeabilization (MOMP), causing the release of cytochrome C into the cytosol, which then activates apoptotic protease activating factor-1 (Apaf-1), initiating caspase activation.

2. Extrinsic Pathway:

   • Triggered by external signals, such as ligands binding to death receptors on the cell surface.

   • Engages BH3-only proteins, like Bid, which connect intrinsic and extrinsic pathways.

   • Activation of caspase-8 links the external signals to mitochondrial events, promoting apoptosis.

Survival Factors and Apoptosis

• Survival factors are essential for regulating apoptosis, providing signals that promote cell survival through:

  • Inhibition of pro-apoptotic factors such as Bax and Bad.

  • Activation of anti-apoptotic proteins such as Bcl-2.

• These factors are critical for nerve development and play a role in preventing neurodegenerative diseases, ensuring optimal cell functioning.

Summary of Apoptosis

• Apoptosis vs. Necrosis:

  • Apoptosis is a regulated and intentional process, whereas necrosis is uncontrolled cell death.

• The significance of apoptosis spans across essential biological functions:

  • Crucial for development, immune responses, and tissue homeostasis.

  • Plays a vital role in maintaining cell populations within tissues and acts as a mechanism for preventing cancer progression by ensuring damaged or unnecessary cells are systematically removed.