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Apoptosis
Intrinsic and Extrinsic Pathways
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Apoptosis is a programmed form of cell death that helps the body remove damaged, infected, or unnecessary cells without causing major inflammation. It is essential in embryonic development, immune system regulation, and cancer prevention. Unlike necrosis, apoptosis is controlled and orderly, with the cell shrinking and breaking into membrane bound fragments. Medical students study apoptosis because failures in this process contribute to cancer, autoimmune disease, and neurodegeneration.
Apoptosis can begin through two main routes: the intrinsic pathway and the extrinsic pathway. The intrinsic pathway is triggered by internal stress such as DNA damage, oxidative stress, or loss of growth factors, and it depends heavily on mitochondria. The extrinsic pathway starts when external death ligands bind to death receptors on the cell surface, activating a signaling cascade. Both pathways converge on executioner caspases, which dismantle the cell by cleaving structural and regulatory proteins.
Key Facts
- Intrinsic apoptosis is driven by mitochondrial outer membrane permeabilization and release of cytochrome c.
- Extrinsic apoptosis begins when FasL, TNF-alpha, or TRAIL binds death receptors such as Fas or TNFR.
- Cytochrome c + Apaf-1 + procaspase-9 -> apoptosome -> active caspase-9.
- Initiator caspases include caspase-8 and caspase-9; executioner caspases include caspase-3, caspase-6, and caspase-7.
- Pro-apoptotic Bcl-2 family members such as Bax and Bak promote apoptosis, while Bcl-2 and Bcl-xL inhibit it.
- p53 can promote apoptosis after DNA damage by increasing expression of pro-apoptotic genes such as Bax, Puma, and Noxa.
Vocabulary
- Apoptosis
- Apoptosis is a regulated process of cell death that removes cells in an orderly way with minimal inflammation.
- Caspase
- A caspase is a protease enzyme that cleaves specific proteins to start or carry out apoptosis.
- Apoptosome
- The apoptosome is a protein complex formed by cytochrome c, Apaf-1, and procaspase-9 that activates caspase-9.
- Death receptor
- A death receptor is a cell surface receptor that triggers the extrinsic apoptotic pathway when bound by its ligand.
- Mitochondrial outer membrane permeabilization
- Mitochondrial outer membrane permeabilization is the formation of pores in the mitochondrial membrane that allows cytochrome c to escape into the cytoplasm.
Common Mistakes to Avoid
- Confusing apoptosis with necrosis, which is wrong because apoptosis is energy dependent and organized, while necrosis is usually uncontrolled and more inflammatory.
- Thinking the intrinsic and extrinsic pathways stay completely separate, which is wrong because they can interact through Bid and converge on the same executioner caspases.
- Assuming all Bcl-2 family proteins promote cell death, which is wrong because some members such as Bcl-2 and Bcl-xL are anti-apoptotic.
- Forgetting that initiator and executioner caspases have different roles, which is wrong because initiator caspases activate the pathway and executioner caspases perform most of the cell dismantling.
Practice Questions
- 1 A researcher exposes cells to a drug that causes mitochondrial membrane permeabilization and cytochrome c release. Which initiator caspase is activated first, and what protein complex forms before it is activated?
- 2 In an experiment, 80 out of 200 cells show activated caspase-3 after Fas ligand treatment. What percentage of cells are undergoing execution phase apoptosis?
- 3 A mutation prevents Fas receptors from binding Fas ligand, but mitochondrial signaling remains normal. Which apoptotic pathway is directly impaired, and how could the cell still undergo apoptosis through the other pathway?