Apoptosis, or programmed cell death, is a crucial process for maintaining tissue homeostasis. It occurs through several pathways, and while sources sometimes list two major pathways, a more comprehensive view identifies three primary routes:
1. Extrinsic (Death Receptor) Pathway
This pathway is initiated by external signals binding to death receptors on the cell surface. These receptors belong to the tumor necrosis factor (TNF) receptor superfamily, including Fas (CD95) and TNF-R1. Ligand binding triggers receptor trimerization, recruiting adaptor proteins (like FADD) and initiating a caspase cascade, ultimately leading to cell death. This pathway is critical in immune responses, eliminating infected or damaged cells.
2. Intrinsic (Mitochondrial) Pathway
The intrinsic pathway, also known as the mitochondrial pathway, is triggered by intracellular stress, such as DNA damage, oxidative stress, or growth factor deprivation. This stress leads to mitochondrial outer membrane permeabilization (MOMP), releasing cytochrome c and other pro-apoptotic factors into the cytoplasm. These factors activate the apoptosome, a protein complex that initiates caspase activation and subsequent cell death. This pathway plays a vital role in eliminating cells with irreparable damage.
3. Cytotoxic Lymphocyte-Initiated Granzyme B Pathway
Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells employ this pathway to eliminate target cells. These immune cells release granzyme B, a serine protease, into the target cell through perforin-mediated pores. Granzyme B directly activates caspases and other apoptotic effectors, triggering cell death without involving the death receptors or mitochondria directly. This pathway is crucial for eliminating virally infected or cancerous cells.
While some sources may simplify to two major pathways (extrinsic and intrinsic), the granzyme B pathway represents a distinct mechanism of caspase activation and should be considered a third key pathway of apoptosis. Each pathway serves a specific role in maintaining cellular balance and organismal health.
