BMS 324: Molecular Genetics and Cell Regulation - Cell Death

Cell Death and Apoptosis

• The growth, development, and maintenance of multicellular organisms depend on the production of cells and mechanisms to destroy them.
• Cell death is not a random process but occurs by a programmed sequence of molecular events.
• Apoptosis (programmed cell death) is a process by which cells die and are engulfed by other cells, including macrophages.

Characteristics of Apoptosis

• Cells dying by apoptosis undergo characteristic morphological changes: • Shrinkage and condensation • Cytoskeleton collapse • Nuclear envelope disassembly • Nuclear chromatin condensation and fragmentation • Cell surface breakdown into membrane-enclosed fragments (apoptotic bodies)

Contrasting Apoptosis with Necrosis

• Apoptosis is distinct from necrosis, a process of cell death caused by acute insults (trauma, lack of blood supply) leading to: • Cell swelling and bursting • Inflammatory response • Energy depletion and metabolic defects • Loss of ionic gradients across the cell membrane

Functional Roles of Apoptosis

• Apoptosis helps sculpt body shape during embryonic development
• Apoptosis eliminates unwanted cells, including: • Abnormal, misplaced, nonfunctional, or potentially dangerous cells • Cells that form structures that are no longer needed (e.g., tadpole tail)
• Apoptosis functions as a quality-control process during development

Regulation of Apoptosis

• The caspase cascade is a self-amplifying and irreversible process
• Two primary activation mechanisms in mammalian cells: • Extrinsic pathway (death receptors, Fas ligand, and Fas death receptor) • Intrinsic pathway (mitochondrial pathway, Bax, Bak, and anti-apoptotic Bcl2 family proteins)

Intrinsic Pathway of Apoptosis

• Cells can activate apoptosis in response to stresses, such as DNA damage
• At least one of the Bax and Bak proteins is required for the intrinsic pathway
• Anti-apoptotic Bcl2 family proteins (Bcl2 and BclXL) inhibit apoptosis by binding to and inhibiting pro-apoptotic Bcl2 family proteins

Inhibitors of Apoptosis (IAPs) and Anti-IAPs

• IAPs bind to and inhibit activated caspases
• Some IAPs polyubiquitylate caspases, marking them for destruction by proteasomes
• Balance between IAPs and anti-IAPs is crucial for controlling apoptosis

Extracellular Survival Factors and Apoptosis

• Most animal cells require continuous signaling from other cells to avoid apoptosis
• Survival factors bind to cell-surface receptors, activating intracellular signaling pathways that suppress apoptosis
• Some survival factors stimulate the synthesis of anti-apoptotic Bcl2 family proteins or inhibit pro-apoptotic BH3-only proteins

Phagocytic Removal of Apoptotic Cells

• Apoptotic cells and their fragments are efficiently eaten by phagocytic cells
• Chemical changes on the surface of apoptotic cells, including the exposure of phosphatidylserine, recruit phagocytic cells

Apoptosis and Disease

• Excessive or insufficient apoptosis can contribute to various diseases
• Examples include autoimmune disease, cancer, and neurodegenerative disorders