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Published online December 17, 2007
doi:10.1083/jcb.200704059
The Journal of Cell Biology, Vol. 179, No. 6, 1163-1177
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Kwong et al.
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Article

 The mitochondrial respiratory chain is a modulator of apoptosis

Jennifer Q. Kwong, Matthew S. Henning, Anatoly A. Starkov, and Giovanni Manfredi

Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10021

Correspondence to Giovanni Manfredi: gim2004{at}med.cornell.edu

Mitochondrial dysfunction and dysregulation of apoptosis are implicated in many diseases such as cancer and neurodegeneration. We investigate here the role of respiratory chain (RC) dysfunction in apoptosis, using mitochondrial DNA mutations as genetic models. Although some mutations eliminate the entire RC, others target specific complexes, resulting in either decreased or complete loss of electron flux, which leads to impaired respiration and adenosine triphosphate (ATP) synthesis. Despite these similarities, significant differences in responses to apoptotic stimuli emerge. Cells lacking RC are protected against both mitochondrial- and endoplasmic reticulum (ER) stress–induced apoptosis. Cells with RC, but unable to generate electron flux, are protected against mitochondrial apoptosis, although they have increased sensitivity to ER stress. Finally, cells with a partial reduction in electron flux have increased apoptosis under both conditions. Our results show that the RC modulates apoptosis in a context-dependent manner independent of ATP production and that apoptotic responses are the result of the interplay between mitochondrial functional state and environmental cues.

Abbreviations used in this paper: AFC, 7-amino-4-trifluormethyl coumarin; BN, blue native; COX, cytochrome c oxidase; CYTB, cytochrome b subunit of complex III; ET, etoposide; H2DCFDA, 2',7'-dichlorofluorescin diacetate; FCCP, carbonylcyanide-p-trifluoromethoxyphenylhydrazone; MERRF, myoclonic epilepsy with ragged red fibers; mtDNA, mitochondrial DNA; NARP, neuropathy, ataxia, and retinitis pigmentosa; PVDF, polyvinylidine fluoride; RC, respiratory chain; ROS, reactive oxygen species; STS, staurosporine; TG, thapsigargin; TMPD, N,N,N',N'-tetramethyl-P-phenylenediamine; TN, tunicamycin; WT, wild type.


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