Chapter 18: Cell Death

Cell Death examines how apoptosis sculpts tissues in embryogenesis, removes superfluous or harmful cells in the immune system, and maintains organ size in adults through tightly regulated cell turnover. The molecular core of apoptosis involves a proteolytic cascade mediated by caspases—cysteine proteases that cleave proteins at specific aspartic acid residues. Two major apoptotic pathways are detailed: the extrinsic pathway, initiated by ligand binding to death receptors like Fas, and the intrinsic mitochondrial pathway, triggered internally by stress signals like DNA damage. Central to the intrinsic pathway is the permeabilization of the mitochondrial outer membrane (MOMP), which releases cytochrome c into the cytosol to form the apoptosome, activating initiator caspase-9. Bcl2 family proteins regulate MOMP, balancing anti-apoptotic members (e.g., Bcl2, BclxL) against pro-apoptotic effectors (Bax, Bak) and BH3-only proteins (e.g., Bad, Bid, Puma). The chapter also discusses inhibitors of apoptosis (IAPs), such as XIAP, and their antagonists Smac and Omi, which fine-tune the caspase activation threshold. Survival signals from the extracellular environment play a critical role in preventing inappropriate apoptosis by suppressing BH3-only proteins or increasing anti-apoptotic Bcl2 proteins. The chapter concludes by examining how apoptosis is executed without triggering inflammation, as apoptotic cells expose phosphatidylserine to attract phagocytes and suppress “don’t eat me” signals. Dysregulation of apoptosis is linked to numerous diseases, including cancer, autoimmune disorders, and neurodegeneration, highlighting the therapeutic potential of drugs like BH3-mimetics that restore the apoptotic balance in cancer cells. Overall, the chapter provides a comprehensive molecular framework for understanding how cells make the life-or-death decision.