BIOS5030 Apoptosis Flashcards

BIOS5030: An Introduction to Apoptosis

Professor Campbell GourlayChapter 18 - Molecular Biology of the Cell (Alberts)

Definition and Origin of Apoptosis

• Etymology: The term "apoptosis" is derived from the ancient Greek words "apo" (meaning "from") and "ptosis" (meaning "falling").

• Coined in 1972 by Andrew H. Wyllie and John Kerr. This term encapsulates the understanding of a crucial biological process involving programmed cell death.

• Related Historical Meanings:

  • James Cormack: Interested in the natural phenomenon of "the falling off of petals from a flower" or leaves from a tree, linking to the life cycle of plants.

  • Hippocrates: Described apoptosis as "the falling off of the bones," indicating an early understanding of cellular demise.

  • Galen: Noted it as "the dropping of the scabs," showcasing an early medical observation of the body’s processes relating to healing and decay.

Apoptosis vs. Necrosis

Cell Death Types:

• Necrosis:

  • Typically triggered by acute injuries (such as infection or trauma) leading to cell swelling, membrane rupture, and subsequent spilling of cell contents into the surrounding tissue, inciting inflammation.

  • The inflammatory response can lead to further tissue damage and chronic inflammation.

• Apoptosis:

  • A physiological process of programmed cell death characterized by a series of morphological and biochemical changes. Cells undergo shrinkage, chromatin condensation, and fragmentation into apoptotic bodies that are swiftly cleared by nearby phagocytic cells.

  • Comparison:

  • Apoptosis: A controlled, energy-dependent, and non-inflammatory process, considered a vital mechanism for cellular turnover and homeostasis.

  • Necrosis: A disorganized, uncontrolled, and inflammatory process associated with significant damage to surrounding tissues.

Importance of Apoptosis

• Apoptosis plays a critical role in maintaining cell and tissue homeostasis. It ensures proper tissue dynamics, preventing excessive cell proliferation that could lead to conditions such as cancer.

• For instance, in an 80-year-old, a lack of apoptosis would result in the accumulation of excessive bone marrow and lymphoid cells, potentially leading to pathological conditions.

• Critical Functions:

  • Prevention of cancer by eliminating genetically damaged or dysfunctional cells.

  • Adaptation during various disease processes, helping the body maintain equilibrium.

  • On average, 50-70 billion cells are eliminated daily through this finely tuned system, underscoring its significance in overall health.

Stimuli for Apoptosis

Numerous factors can initiate apoptosis, including but not limited to:

• Withdrawal of growth factors necessary for cell survival.

• DNA damage from environmental stresses, such as UV light exposure (e.g., sunburn).

• Disruption of cytoskeletal integrity, often induced by chemotherapeutic agents.

• Endoplasmic reticulum (ER) dysfunction due to unfolded protein response.

• Oxidative stress from free radicals leading to cellular injury.

• Tissue ischemia followed by reperfusion injury, commonly seen post-heart attacks.

Developmental Roles of Apoptosis

• Apoptosis is essential during various stages of development, including:

  • Metamorphosis: E.g., the transformation of a tadpole into a frog wherein certain cells must be eliminated for others to develop.

  • Tissue and organ formation: Critical events like digit formation depend on apoptotic cell death to sculpt anatomical structures.

  • Nervous system development: Key for the pruning of neurons, ensuring proper wiring and function of the nervous system.

Genetic Control of Apoptosis

• The C. elegans model organism has provided pivotal insights into apoptosis. Robert Horvitz identified key "cell death genes" (Ced genes) essential for regulating this process.

• Notably, a consistent pattern was observed where 131 specific cells undergo apoptosis during development, highlighting an organized and programmed aspect of cellular life cycles.

Caspase Pathway

• Caspases are a family of cysteine proteases that serve as the main effectors in apoptosis.

  • Initiator caspases: Such as caspase-8 and caspase-9, play a role in the initial activation of downstream executioner caspases (e.g., caspase-3).

  • A cascade of signals is amplified through this pathway, leading to organized cellular dismantling.

Morphological Changes During Apoptosis

Distinct morphological changes associated with apoptosis include:

• Membrane blebbing: The outer membrane begins to bulge (blebs out) as phospholipids within the membrane undergo flipping.

• Changes in nuclear morphology: Including chromatin condensation and fragmentation.

• Phagocytosis: Apoptotic bodies are recognized and engulfed by neighboring cells, preventing inflammation and maintaining tissue integrity.

Pathways of Apoptosis

• Intrinsic Pathway:

  • Involves mitochondrial outer membrane permeabilization (MOMP), where cytochrome c is released and activates apoptosomes that subsequently recruit and activate caspases.

• Extrinsic Pathway:

  • Initiated through death receptors located on the cell surface which, upon activation, can induce MOMP via proteins like Bid, thus integrating both intrinsic and extrinsic signals.

Role of Survival Factors

• Extracellular signals that inhibit apoptosis play essential roles by:

  • Increasing the production of survival factors that help cells resist apoptosis.

  • Inactivating apoptotic proteins such as Inhibitor of Apoptosis Proteins (IAPs) and pro-apoptotic members of the Bcl2 family.

  • These survival factors are particularly critical during neurodevelopment, ensuring that essential neuronal populations are not lost to excessive apoptosis.

Summary of Key Points

• Apoptosis is a highly regulated process, distinct from necrosis, governed by complex genetic and biochemical pathways.

• It can be triggered through both intrinsic and extrinsic signaling pathways that converge to execute programmed cell death.

• This process is vital for maintaining proper cell numbers, facilitating immune responses, and preserving tissue homeostasis under physiological conditions.

• Understanding apoptosis has broad implications for treatment strategies in cancer, neurodegenerative diseases, and regenerative medicine.