Cytochrome c Maintains Mitochondrial Transmembrane Potential and ATP Generation after Outer Mitochondrial Membrane Permeabilization during the Apoptotic Process

doi:10.1083/jcb.153.2.319

Published online 16 April 2001. doi:10.1083/jcb.153.2.319

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© The Rockefeller University Press, 0021-9525/2001/4/319/ $5.00
The Journal of Cell Biology, Volume 153, Number 2, April 16, 2001 319-328

Original Article

Cytochrome c Maintains Mitochondrial Transmembrane Potential and ATP Generation after Outer Mitochondrial Membrane Permeabilization during the Apoptotic Process

Nigel J. Waterhouse^a, Joshua C. Goldstein^a, Oliver von Ahsen^a, Martin Schuler^a, Donald D. Newmeyer^a, and Douglas R. Green^a
^a Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121

Correspondence to: Douglas R. Green, La Jolla Institute for Allergy and Immunology, 10355 Science Center Dr., San Diego, CA 92121. Tel:(858) 558-3500 Fax:(858) 558-3526 E-mail:DGreen5240{at}aol.com.

During apoptosis, cytochrome c is released into the cytosolas the outer membrane of mitochondria becomes permeable, andthis acts to trigger caspase activation. The consequences ofthis release for mitochondrial metabolism are unclear. Usingsingle-cell analysis, we found that when caspase activity isinhibited, mitochondrial outer membrane permeabilization causesa rapid depolarization of mitochondrial transmembrane potential,which recovers to original levels over the next 30–60min and is then maintained. After outer membrane permeabilization,mitochondria can use cytoplasmic cytochrome c to maintain mitochondrialtransmembrane potential and ATP production. Furthermore, bothcytochrome c release and apoptosis proceed normally in cellsin which mitochondria have been uncoupled. These studies demonstratethat cytochrome c release does not affect the integrity of themitochondrial inner membrane and that, in the absence of caspaseactivation, mitochondrial functions can be maintained afterthe release of cytochrome c.

Key Words: apoptosis, mitochondria, membrane potential, caspases, ATP

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