Apoptosis and Cell Death Mechanisms

Apoptosis

• Cell death is vital for animal and plant development, continuing into adulthood.
• In a healthy adult human, billions of cells die every hour in the bone marrow and intestines.
• Tissue size remains consistent as cell division balances cell death.
• Normal cell death is a form of cellular suicide.
• Cells undergo a controlled death process called programmed cell death.

Apoptosis: Definition

• Apoptosis is the main type of programmed cell death.
• It originates from the Greek word meaning "falling off."
• Apoptotic cells have altered cell surfaces, enabling rapid engulfment by macrophages before spillage of their contents.
• This protects against damaging inflammation.

Apoptosis: Morphology

• Apoptotic cells display distinctive morphological changes.
• Cells shrink and condense.
• Cytoskeleton structure disintegrates.
• Nuclear chromatin condenses and breaks into fragments.
• Large cells often fragment into membrane-bound apoptotic bodies.
• Cell surface or apoptotic bodies' chemistry alters.

Apoptosis: Classical Examples

• Crucial in animal development for shaping structures like hands and feet, and regulating nervous system cells.
• Contributes to the development of adaptive immune system components.
• In metamorphosis, eliminating unnecessary cells.
• In adult tissues, removing malfunctioning or dangerous cells.
• Essential for eliminating cells no longer needed following infections.
• Maintains a ready pool of short-lived immune cells, like neutrophils in bone marrow.

Apoptosis: Biochemistry

• Biochemical changes help identify apoptotic cells.
• During apoptosis, endonuclease fragments DNA into unique sizes.
• These DNA fragments form a characteristic "ladder" pattern in gel electrophoresis.
• Phosphatidylserine, a negatively charged phospholipid, moves from the inner to the outer leaflet of the cell membrane, acting as a marker for engulfment.
• Loss of transmembrane potential in mitochondria, releasing cytochrome c.

Apoptosis Machinery

• Apoptosis relies on a family of caspase proteases.
• Caspases have a cysteine at their active site and cleave aspartic acid residues.
• Caspases are initially inactive precursors (procaspases).
• Proteolytic cleavage activates them.

Apoptosis: The Beginning

• Healthy cells constantly produce procaspases.
• Procaspase activation requires an initiating trigger.
• Initiator procaspases contain a prodomain with a caspase recruitment domain (CARD).
• CARDs allow assembly with adaptor proteins and activation complexes when required.
• Once initiator procaspases are close together, they activate each other, making the process irreversible.

Procaspase Activation

• Procaspases have large and small subunits.
• Subunits form a heterodimer that then combines with another to make a functional active tetramer.
• The first activated procaspases are initiator procaspases, activating subsequent executioner procaspases.
• Executioner caspases cleave essential proteins in the cell, leading to its demise.

Not all caspases mediate apoptosis

• Some caspases play roles in inflammation.
• Caspases involved in apoptosis fall into initiator (e.g., caspase 8, 9) and executioner (e.g., caspase 3, 7) groups.

Target Proteins

• Executioner caspases cleave target proteins, affecting the nuclear lamina, endonucleases, cytoskeleton, and cell-cell adhesion proteins.

Signaling Pathways (Extrinsic)

• Cell surface Fas death receptors trigger the extrinsic pathway.
• They belong to the TNF receptor family.
• Receptors are homotrimers with extracellular ligand-binding domains, a transmembrane domain, and intracellular death domains.
• They are activated by external signals.

Signaling Pathways (Intrinsic)

• Intrinsic pathways are activated by internal stimuli, such as DNA damage, lack of oxygen, or nutrient deprivation.
• Mitochondria release cytochrome c, initiating the intrinsic pathway through the activation of Apaf1.
• Apaf1 binds with cytochorome c and procaspase-9 to form the apoptosome.

Regulation Intrinsic Pathway

• Bcl2 proteins tightly control the intrinsic pathway.
• Different Bcl2 family members regulate the balance between apoptosis and survival.
• Pro-apoptotic members (BH123) instigate apoptosis upon activation.
• Anti-apoptotic (e.g., Bcl2) members prevent apoptosis.
• BH3-only proteins are a crucial regulatory link between anti- and pro-apoptotic Bcl2 proteins.

Regulation Intrinsic Pathway IAPs

• IAPs (inhibitors of apoptosis) are proteins that prevent excessive apoptosis.
• They bind to and inhibit activated caspases, preventing uncontrolled processes.
• Anti-IAPs are also present and can overcome this inhibition for programmed cell death.

Extracellular Survival Factors

• Survival factors can either inhibit or facilitate apoptosis, in large part from their interactions with intracellular molecules and pathways.

Summary

• Inappropriate apoptosis can contribute to various diseases.
• Imbalances in apoptosis, either too much or too little, significantly impact the body's health.
• Different cell death pathways control excessive or deficient apoptosis across the human body.

This quiz explores the fundamental concepts of apoptosis, including the roles of phosphatidylserine and caspases, changes in chromosomal DNA, and the significance of mitochondrial membrane potential. Test your knowledge on the morphological characteristics and implications of apoptosis in development and adult tissues.