Mitochondrial Control of Apoptosis

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:

• Brenner D, Mak TW (2009) Mitochondrial cell death effectors. Curr. Opin. Cell Biol. 21(6), 871–7.
• Chalah A, Khosravi-Far R (2008) The mitochondrial death pathway. Adv. Exp. Med. Biol. 615, 25–45.
• Lindsay J, Esposti MD, Gilmore AP (2011) Bcl-2 proteins and mitochondria--specificity in membrane targeting for death. Biochim. Biophys. Acta 1813(4), 532–9.
• Ola MS, Nawaz M, Ahsan H (2011) Role of Bcl-2 family proteins and caspases in the regulation of apoptosis. Mol. Cell. Biochem. 351(1-2), 41–58.
• Pradelli LA, Bénéteau M, Ricci JE (2010) Mitochondrial control of caspase-dependent and -independent cell death. Cell. Mol. Life Sci. 67(10), 1589–97.
• Rong Y, Distelhorst CW (2008) Bcl-2 protein family members: versatile regulators of calcium signaling in cell survival and apoptosis. Annu. Rev. Physiol. 70, 73–91.
• Speidel D (2010) Transcription-independent p53 apoptosis: an alternative route to death. Trends Cell Biol. 20(1), 14–24.
• Suen DF, Norris KL, Youle RJ (2008) Mitochondrial dynamics and apoptosis. Genes Dev. 22(12), 1577–90.

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

created September 2008

revised November 2012