Mitochondrial apoptosis-induced channel

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Release of cytochrome c through MAC[1]

The Mitochondrial Apoptosis-Induced Channel (or MAC), is an early marker of the onset of apoptosis.[2][3]  This ion channel is formed on the outer mitochondrial membrane in response to certain apoptotic stimuli.[4]  MAC activity is detected by patch clamping mitochondria from apoptotic cells at the time of cytochrome c release.[5]

Members of the Bcl-2 protein family regulate apoptosis by controlling the formation of MAC: the pro-apoptotic members Bax and/or Bak form MAC,[1][5] whereas the anti-apoptotic members like Bcl-2 or Bcl-xL prevent MAC formation.  Once formed, MAC mediates the release of cytochrome c to the cytosol, triggering the commitment step of the mitochondrial apoptotic cascade.  Depletion of MAC activity is accomplished pharmacologically by specific compounds, namely Bax Channel Inhibitors[6] and MAC inhibitors.[7]  Either by knocking down MAC’s main components or by its pharmacological inhibition, the end result is prevention of cytochrome c release and apoptosis.

References[edit]

  1. ^ a b Laurent M. Dejean, Sonia Martinez-Caballero, Stephen Manon, Kathleen W. Kinnally (2006). "Regulation of the mitochondrial apoptosis-induced channel, MAC, by BCL-2 family proteins.". Biochim Biophys Acta 1762 (2): 191–201. doi:10.1016/j.bbadis.2005.07.002. PMID 16055309. 
  2. ^ Evgeny V. Pavlov, Muriel Priault, Dawn Pietkiewicz, Emily H.-Y. Cheng, Bruno Antonsson, Stephen Manon, Stanley J. Korsmeyer, Carmen A. Mannella, and Kathleen W. Kinnally (2001). "A novel, high conductance channel of mitochondria linked to apoptosis in mammalian cells and Bax expression in yeast". J. Cell Biol. 155 (5): 725–732. doi:10.1083/jcb.200107057. PMC 2150879. PMID 11724814. 
  3. ^ Liang Guo, Dawn Pietkiewicz, Evgeny V. Pavlov, Sergey M. Grigoriev, John J. Kasianowicz, Laurent M. Dejean, Stanley J. Korsmeyer, Bruno Antonsson, and Kathleen W. Kinnally (2004). "Effects of cytochrome c on the mitochondrial apoptosis-induced channel MAC". Am. J. Physiol. Cell. Physiol. 286 (5): C1109–C1117. doi:10.1152/ajpcell.00183.2003. PMID 15075210. 
  4. ^ Laurent M. Dejean, Sonia Martinez-Caballero, Kathleen W. Kinnally (2006). "Is MAC the knife that cuts cytochrome c from mitochondria during apoptosis?". Cell Death and Differentiation 13 (8): 1387–1395. doi:10.1038/sj.cdd.4401949. PMID 16676005. 
  5. ^ a b Laurent M. Dejean, Sonia Martinez-Caballero, Liang Guo, Cynthia Hughes, Oscar Teijido, Thomas Ducret, François Ichas, Stanley J. Korsmeyer, Bruno Antonsson, Elizabeth A. Jonas, and Kathleen W. Kinnally (2005). "Oligomeric Bax Is a Component of the Putative Cytochrome c Release Channel MAC, Mitochondrial Apoptosis-induced Channel". Mol. Biol. Cell 16 (5): 2424–2432. doi:10.1091/mbc.E04-12-1111. PMC 1087246. PMID 15772159. 
  6. ^ Claudio Hetz, Pierre-Alain Vitte, Agnes Bombrun, Tatiana K. Rostovtseva, Sylvie Montessuit, Agnes Hiver, Matthias K. Schwarz, Dennis J. Church, Stanley J. Korsmeyer, Jean-Claude Martinou, Bruno Antonsson (2005). "Bax Channel Inhibitors Prevent Mitochondrion-mediated Apoptosis and Protect Neurons in a Model of Global Brain Ischemia". J. Biol. Chem. 280 (52): 42960–42970. doi:10.1074/jbc.M505843200. PMID 16219766. 
  7. ^ Pablo M. Peixoto, Shin-Young Ryu, Agnes Bombrun, Bruno Antonsson, Kathleen W. Kinnally (2009). "MAC inhibitors suppress mitochondrial apoptosis". Biochem. J. 280 (3): 381–7. doi:10.1042/BJ20090664. PMID 19691447.