A novel, high conductance channel of mitochondria linked to apoptosis in mammalian cells and Bax expression in yeast

doi:10.1083/jcb.200107057

Published 26 November 2001. doi:10.1083/jcb.200107057

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© The Rockefeller University Press, 0021-9525/2001/11/725 $5.00
The Journal of Cell Biology, Volume 155, Number 5, November 26, 2001 725-732

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A novel, high conductance channel of mitochondria linked to apoptosis in mammalian cells and Bax expression in yeast

Evgeny V. Pavlov¹, Muriel Priault², Dawn Pietkiewicz¹, Emily H.-Y. Cheng³, Bruno Antonsson⁴, Stephen Manon², Stanley J. Korsmeyer³, Carmen A. Mannella⁵ and Kathleen W. Kinnally¹

¹ Division of Basic Sciences, New York University College of Dentistry, New York, NY 10010
² Institut de Biochimie et Génétique Cellulaires/Centre National de la Recherche Scientifique, F-33077 Bordeaux, France
³ Departments of Pathology and Medicine, Harvard Medical School, Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Boston, MA 02115
⁴ Serono Pharmaceutical Research Institute, Serono International S.A., CH-1228 Plan-les Ouates, Geneva, Switzerland
⁵ Wadsworth Center, New York State Department of Health, Albany, NY 12203

Address correspondence to Kathleen W. Kinnally, Division of Basic Sciences, New York University College of Dentistry, 345 East 24th St., New York, NY 10010. Tel.: (212) 998-9445. Fax: (212) 995-4087. E-mail: kathleen.kinnally{at}nyu.edu

During apoptosis, proapoptotic factors are released from mitochondriaby as yet undefined mechanisms. Patch-clamping of mitochondriaand proteoliposomes formed from mitochondrial outer membranesof mammalian (FL5.12) cells has uncovered a novel ion channelwhose activity correlates with onset of apoptosis. The porediameter inferred from the largest conductance state of thischannel is $~$ 4 nm, sufficient to allow diffusion of cytochromec and even larger proteins. The activity of the channel is affectedby Bcl-2 family proteins in a manner consistent with their pro-or antiapoptotic properties. Thus, the channel activity correlateswith presence of proapoptotic Bax in the mitochondrial outermembrane and is absent in mitochondria from cells overexpressingantiapoptotic Bcl-2. Also, a similar channel activity is foundin mitochondrial outer membranes of yeast expressing human Bax.These findings implicate this channel, named mitochondrial apoptosis–inducedchannel, as a candidate for the outer-membrane pore throughwhich cytochrome c and possibly other factors exit mitochondriaduring apoptosis.

Key Words: apoptosis; mitochondria; channels; Bax; patch-clamp

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