Mitochondrial apoptosis-induced channel

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]

Release of cytochrome c through MAC[1]

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
  1. 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 & 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 & 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. Laurent M. Dejean; Sonia Martinez-Caballero; Liang Guo; Cynthia Hughes; Oscar Teijido; Thomas Ducret; François Ichas; Stanley J. Korsmeyer; Bruno Antonsson; Elizabeth A. Jonas & 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. 423 (3): 381–7. doi:10.1042/BJ20090664. PMID 19691447.
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