Assembly of the Mitochondrial Apoptosis-induced Channel, MAC

• Published in: The Journal of biological chemistry Vol. 284; no. 18; pp. 12235 - 12245
• Main Authors: Martinez-Caballero, Sonia, Dejean, Laurent M., Kinnally, Michael S., Oh, Kyoung Joon, Mannella, Carmen A., Kinnally, Kathleen W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2009; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Apoptosis - physiology; bcl-2 Homologous Antagonist-Killer Protein - genetics; bcl-2 Homologous Antagonist-Killer Protein - metabolism; bcl-2-Associated X Protein - chemistry; bcl-2-Associated X Protein - genetics; bcl-2-Associated X Protein - metabolism; BH3 Interacting Domain Death Agonist Protein - chemistry; BH3 Interacting Domain Death Agonist Protein - genetics; BH3 Interacting Domain Death Agonist Protein - metabolism; Cell Line; Cytochromes c - genetics; Cytochromes c - metabolism; Liposomes - chemistry; Mice; Mice, Knockout; Mitochondria - genetics; Mitochondria - metabolism; Mitochondrial Membrane Transport Proteins; Mitochondrial Membranes - metabolism; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Models, Biological; Permeability; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Voltage-Dependent Anion Channel 1 - genetics; Voltage-Dependent Anion Channel 1 - metabolism; Voltage-Dependent Anion Channels - genetics; Voltage-Dependent Anion Channels - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M806610200

Although Bcl-2 family proteins control intrinsic apoptosis, the mechanisms underlying this regulation are incompletely understood. Patch clamp studies of mitochondria isolated from cells deficient in one or both of the pro-apoptotic proteins Bax and Bak show that at least one of the proteins must be present for formation of the cytochrome c-translocating channel, mitochondrial apoptosis-induced channel (MAC), and that the single channel behaviors of MACs containing exclusively Bax or Bak are similar. Truncated Bid catalyzes MAC formation in isolated mitochondria containing Bax and/or Bak with a time course of minutes and does not require VDAC1 or VDAC3. Mathematical analysis of the stepwise changes in conductance associated with MAC formation is consistent with pore assembly by a barrel-stave model. Assuming the staves are two transmembrane α-helices in Bax and Bak, mature MAC pores would typically contain ∼9 monomers and have diameters of 5.5–6 nm. The mitochondrial permeability data are inconsistent with formation of lipidic pores capable of transporting megadalton-sized macromolecules as observed with recombinant Bax in liposomes.