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Vol. 16, Issue 5, 2424-2432, May 2005
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* Department of Basic Sciences, College of Dentistry, New York University, New York, NY 10010;
Institut National de la Santé et de la Recherche Médicale, Centre de Lutte Contre le Cancer Bergonié and Institut Européen de Chimie et Biologie, 33600 Pessac, France;
Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115;
Serono Pharmaceutical Research Institute, Serono International S. A., Geneva, Switzerland; and
|| Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520
Submitted December 23, 2004;
Revised February 7, 2005;
Accepted February 28, 2005
Monitoring Editor: Donald Newmeyer
Bcl-2 family proteins regulate apoptosis, in part, by controlling formation of the mitochondrial apoptosis-induced channel (MAC), which is a putative cytochrome c release channel induced early in the intrinsic apoptotic pathway. This channel activity was never observed in Bcl-2–overexpressing cells. Furthermore, MAC appears when Bax translocates to mitochondria and cytochrome c is released in cells dying by intrinsic apoptosis. Bax is a component of MAC of staurosporine-treated HeLa cells because MAC activity is immunodepleted by Bax antibodies. MAC is preferentially associated with oligomeric, not monomeric, Bax. The single channel behavior of recombinant oligomeric Bax and MAC is similar. Both channel activities are modified by cytochrome c, consistent with entrance of this protein into the pore. The mean conductance of patches of mitochondria isolated after green fluorescent protein-Bax translocation is significantly higher than those from untreated cells, consistent with onset of MAC activity. In contrast, the mean conductance of patches of mitochondria indicates MAC activity is present in apoptotic cells deficient in Bax but absent in apoptotic cells deficient in both Bax and Bak. These findings indicate Bax is a component of MAC in staurosporine-treated HeLa cells and suggest Bax and Bak are functionally redundant as components of MAC.
Abbreviations used: GFP-Bax, green fluorescence protein-tagged Bax; IL-3, interleukin-3; MAC, mitochondrial apoptosis-induced channel; PTP, permeability transition pore; VDAC, voltage-dependent anion-selective channel.
Address correspondence to: Kathleen W. Kinnally (kck1{at}nyu.edu).
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