Apoptosis, also known as programmed cell death, is a crucial physiological process essential for the development, homeostasis, and elimination of damaged cells in multicellular organisms. It is triggered by various factors such as DNA damage, cellular stress, or signaling from neighboring cells. Apoptosis happens in creatures with multiple cells and certain eukaryotic, single-celled microorganisms. This highly regulated process involves distinct morphological shifts, like cell shrinkage, chromatin condensation, and apoptotic body generation. Apoptosis dysregulation can lead to a wide range of severe illnesses, including neurodegenerative diseases, autoimmune disorders, and cancers.
The extrinsic pathway is initiated by external signals, like ligands attaching to cell surface death receptors. Examples of death receptors include tumor necrosis factor receptor 1 (TNFR1), and Fas receptor. Upon ligand binding, death receptors undergo conformational changes and recruit adaptor proteins like FADD (Fas-associated death domain) and TRADD (TNFR1-associated death domain), forming the death-inducing signaling complex (DISC). This complex activates initiator caspase-8 through proximity-induced autoactivation. Activated caspase-8 then initiates a caspase cascade by cleaving and activating downstream effector caspases like caspase-3, ultimately leading to cell death.
The intrinsic pathway, additionally referred to as the mitochondrial pathway, is triggered by internal cellular stress signals including oxidative stress, DNA damage, or growth factor withdrawal. These signals lead to the permeabilization of the mitochondrial outer membrane (MOMP), resulting in the release of pro-apoptotic factors such as cytochrome c from the intermembrane space of the mitochondria into the cytoplasm. Cytochrome c interacts with apoptotic protease activating factor-1 (Apaf-1) to form the apoptosome complex, which triggers initiator caspase-9. Activated caspase-9 then breaks down and triggers downstream effector caspases like caspase-3, initiating the apoptotic process.
The execution pathway involves the stimulation of effector caspases, notably caspase-3, which cleaves various cellular substrates critical for cell integrity and function. These substrates include structural proteins, DNA repair enzymes, and inhibitors of DNA fragmentation. The cleavage of these substrates leads to characteristic morphological changes associated with apoptosis, such as DNA fragmentation, chromatin condensation, cell membrane blebbing, and formation of apoptotic bodies.
Fig.1 The molecular activation mechanism of intrinsic and extrinsic pathways of apoptosis.1
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| Extrinsic pathway | DR3, DR3, DR5, TNF-α, TNFR1, FasL, FasR, Apo3L, Apo2L, FADD, TRADD, RIP, DED, caspase-8, c-FLIP, BIRC2, DIABLO, XIAP, TRAF3, TRAF4, TRAF6 |
| Intrinsic pathway | Bcl-w, Bcl-XS, Bcl-XL, Bcl-x, Bcl-2, BAD, BID, BAG, BAK1, BAX, Bcl-10, BAG, CAD, AIF, BIM, Myc, BIK, Blk, Aven, Noxa, Puma, Smac/DIABLO, HtrA2/Omi, IAP, Apaf-1, Caspase-9 |
| Execution pathway | Caspase-3, Caspase-6, Caspase-7, Caspase-10, Caspase-14, Caspase-16, ICAD, CAD, PARP, Alpha fodrin, NuMA |
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