Apoptosis

Apoptosis is a form of programmed cell death that enables the orderly elimination of cells without provoking an inflammatory response. It features cell shrinkage, chromatin condensation, DNA fragmentation, membrane blebbing, and the formation of apoptotic bodies that are promptly cleared by phagocytes.

Two major signaling pathways activate a family of proteases called caspases, which execute the death program. The intrinsic (mitochondrial) pathway responds to cellular stress, causes mitochondrial outer membrane permeabilization, cytochrome c release, formation of the apoptosome with Apaf-1, and activation of initiator caspase-9, which then activates executioner caspases.

The extrinsic (death receptor) pathway begins with ligands such as Fas ligand or TNF-related ligands binding to death receptors (e.g., Fas, TNFR), recruiting adaptor proteins like FADD, and activating initiator caspase-8 (or caspase-10). Caspase-8 can directly activate executioners or amplify the intrinsic pathway by cleaving Bid.

Executioner caspases, including caspase-3, caspase-6, and caspase-7, dismantle the cell by cleaving substrates, leading to DNA fragmentation and apoptotic body formation. DNA fragmentation is mediated by caspase-activated DNase (CAD) after inhibition by iCAD. Phagocytes engulf apoptotic bodies with little or no inflammation.

Apoptosis plays a fundamental role in development, tissue homeostasis, and immune regulation, as well as in removing damaged or potentially oncogenic cells. Dysregulation is associated with cancer, neurodegenerative disease, autoimmune conditions, and infections; therapies may aim to promote or inhibit apoptosis depending on the context.