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Mitochondrial Control of Apoptosis

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Mitochondrial Control of Apoptosis

Pathway Description:

The Bcl-2 family of proteins regulate apoptosis by controlling mitochondrial permeability. The anti-apoptotic proteins Bcl-2 and Bcl-xL reside in the outer mitochondrial wall and inhibit cytochrome c release. The pro-apoptotic Bcl-2 proteins Bad, Bid, Bax, and Bim may reside in the cytosol but translocate to mitochondria following death signaling, where they promote the release of cytochrome c. Bad translocates to mitochondria and forms a pro-apoptotic complex with Bcl-xL. This translocation is inhibited by survival factors that induce the phosphorylation of Bad, leading to its cytosolic sequestration. Cytosolic Bid is cleaved by caspase-8 following signaling through Fas; its active fragment (tBid) translocates to mitochondria. Bax and Bim translocate to mitochondria in response to death stimuli, including survival factor withdrawal. Activated following DNA damage, p53 induces the transcription of Bax, Noxa, and Puma. Upon release from mitochondria, cytochrome c binds to Apaf-1 and forms an activation complex with caspase-9. Although the mechanism(s) regulating mitochondrial permeability and the release of cytochrome c during apoptosis are not fully understood, Bcl-xL, Bcl-2, and Bax may influence the voltage-dependent anion channel (VDAC), which may play a role in regulating cytochrome c release. Mule/ARF-BP1 is a DNA damage-activated E3 ubiquitin ligase for p53, and Mcl-1, an anti-apoptotic member of Bcl-2.

Selected Reviews:

We would like to thank Prof. Junying Yuan, Harvard Medical School, Boston, MA, for reviewing this diagram.

created September 2008

revised November 2012

Acetylase
Acetylase
Metabolic Enzyme
Metabolic Enzyme
Adaptor
Adaptor
Methyltransferase or G-protein
Methyltransferase or G-protein
Adaptor
Apoptosis/Autophagy Regulator
Phosphatase
Phosphatase
Cell Cycle Regulator
Cell Cycle Regulator
Protein Complex
Protein Complex
Deacetylase or Cytoskeletal Protein
Deacetylase or Cytoskeletal Protein
Ubiquitin/SUMO Ligase or Deubiquitinase
Ubiquitin/SUMO Ligase or Deubiquitinase
Growth Factor/Cytokine/Development Protein
Growth Factor/Cytokine/Development Protein
Transcription Factor or Translation Factor
Transcription Factor or Translation Factor
GTPase/GAP/GEF
GTPase/GAP/GEF
Receptor
Receptor
Kinase
Kinase
Other
Other
 
Direct Process
Direct Process
Tentative Process
Tentative Process
Translocation Process
Translocation Process
Stimulatory Modification
Stimulatory Modification
Inhibitory Modification
Inhibitory Modification
Transcriptional Modification
Transcriptional Modification