Electrophysiology of the Mitochondrial Apoptosis-Induced Channel, MAC

MAC is distinct from typical ion channels in its huge pore diameter of 4–6 nm and poor ion selectivity. Although it has been identified during intracellular recordings, MAC is typically studied by patch-clamping mitochondria isolated from apoptotic cells. This mega-channel assembles in the outer membrane of mitochondria containing the pro-apoptotic proteins Bax and/or Bak in response to apoptotic signals. Typically, MAC formation requires assembly of 8–10 molecules of Bax and/or Bak within the outer membrane to achieve a pore size sufficient to release folded 3 nm cytochrome c from the space between the mitochondrial inner and outer membranes. Several compounds have been identified as MAC activators, e.g., BH3-only mimetics, and MAC inhibitors, e.g. iMAC2, and these small molecules are being used to further dissect the apoptotic process. MAC is a novel therapeutic target for a variety of diseases including cancer, infarcts, and neurodegenerative diseases.