KINE 1000 Lecture 2: Intrinsic Pathway of Apoptosis Depends on Mitochondria
4 Jun 2018
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Intrinsic Pathway of Apoptosis Depends on
Mitochondria
• Responses to stresses, DNA damange activate apoptosis inside cell
• Intrinsic pathway depends on release of mitochondrial proteins into cytosol that
normally reside in intermembrane space. Released proteins active caspase proteolytic
cascade in cytoplasm leading to apoptosis
• Cytochrome C, is protein involved in mitochondrial ETC. When released in cytosol it has
new function
- Cytochrome c binds to adaptor protein called Apaf1 causing its oligomerization into
a heptamer called apoptosome. Apaf1 proteins in apoptosome recruit initator
caspases-9-proteins.
- Activate Caspase-9-molecuels activate downstream executioner caspases to induce
apoptosis
Bcl1 Proteins Regulate Intrinsic Pathway
• Intrinsic pathway of apoptosis is regulated to ensure that cells kill themselves when
appropriate
• Intracellular reuglulators of Intrinsic pathway is Bc12 family
• Bcl1 proteins regulate intrinsic pathway by controlling release of cytochrome c & other
intermembrane mitochondrial proteins in cytosol
• Bcl1 family proteins are pro-apoptotic → promote apoptotic by ehnacing release of
proteins
• Anti-apoptotic → inhibit apoptosis by blocking release
• Pro & anti-apoptotic proteins bind with each other in various combinations to form
heterodiers where proteis ihiit eah other’s futio. Balae of two futioal
classes of Bcl2 proteins determines if cell lives or dies by intrinsic pathway
• When apoptotic stimuli triggers intrinsic pathway, pro-apoptotic effector Bcl12 family
proteins become activated-- > induced release of cytochrome c & other intermembrane
proteins
- Bax & Bak are main effector Bcl1 proteins
- Lack of both proteins are resistant to all pro-apoptotic signals
- Bak is bound to mitochondria outer membrane & Bax in cytosol
- Apoptotic stimuli → pro-apoptotic proteins (BH3-only) →Pro-apoptotic effector
Bcl12 proteins → induce cytochrome c r& other intermembrane protein release
• Anti-apoptotic Bcl2 Proteins Bcl2 & BclXL are located on cytosolic surface of outer
mitochondrial membrane where they prevent inappropriate release of intermembrane
proteins
- Inhibits apoptosis by binding & inhibiting pro-apoptotic bcl2 proteins.
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