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Mitochondria participate in apoptotic signaling pathways through the release of mitochondrial proteins into the cytoplasm. Cytochrome c, a key protein in electron transport, is released from mitochondria in response to apoptotic signals, and activates Apaf-1, a protease released from mitochondria. Activated Apaf-1 activates caspase-9 and the rest of the caspase pathway. Smac/DIABLO is released from mitochondria and inhibits IAP proteins that normally interact with caspase-9 to inhibit apoptosis. Apoptosis regulation by Bcl-2 family proteins occurs as family members form complexes that enter the mitochondrial membrane, regulating the release of cytochrome c and other proteins. TNF family receptor that cause apoptosis directly activate the caspase cascade, but can also activate Bid, a Bcl-2 family member, which activates mitochondria-mediated apoptosis. Bax, another Bcl-2 family member, is activated by this pathway to localize to the mitochondrial membrane and increase its permeability, releasing cytochre c and other mitochondrial proteins. Bcl-2 and Bcl-xL prevent pore formation, blocking apoptosis. AIF (Apoptosis inducing factor) is another mitochondrial factor that is released into the cytoplasm to induce apoptosis. AIF-induced apoptosis is important during development but is not caspase dependent. |
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Glenn Croston, PhD |
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Harris M.H. and Thompson C.B. The role of the Bcl-2 family in the regulation of outer mitochondrial membrane permeability. Cell Death Differ 2000 Dec;7(12):1182-91
Joza N. et al. Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Nature 2001 Mar 29;410(6828):549-54
Shi Y. A structural view of mitochondria-mediated apoptosis. Nat Struct Biol 2001 May;8(5):394-401
Srinivasula, S.M. A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis. Nature 2001 Mar 1;410(6824):112-6
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