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Flux control of cytochrome c oxidase in human skeletal muscle

Kunz, Wolfram S. and Kudin, Alexei and Vielhaber, Stefan and Elger, Christian E. and Attardi, Giuseppe and Villani, Gaetano (2000) Flux control of cytochrome c oxidase in human skeletal muscle. Journal of Biological Chemistry, 275 (36). pp. 27741-27745. ISSN 0021-9258. https://resolver.caltech.edu/CaltechAUTHORS:KUNjbc00

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Abstract

In the present work, by titrating cytochrome c oxidase (COX) with the specific inhibitor KCN, the flux control coefficient and the metabolic reserve capacity of COX have been determined in human saponin-permeabilized muscle fibers. In the presence of the substrates glutamate and malate, a 2.3 ± 0.2-fold excess capacity of COX was observed in ADP-stimulated human skeletal muscle fibers. This value was found to be dependent on the mitochondrial substrate supply. In the combined presence of glutamate, malate, and succinate, which supported an approximately 1.4-fold higher rate of respiration, only a 1.4 ± 0.2-fold excess capacity of COX was determined. In agreement with these findings, the flux control of COX increased, in the presence of the three substrates, from 0.27 ± 0.03 to 0.36 ± 0.08. These results indicate a tight in vivo control of respiration by COX in human skeletal muscle. This tight control may have significant implications for mitochondrial myopathies. In support of this conclusion, the analysis of skeletal muscle fibers from two patients with chronic progressive external ophthalmoplegia, which carried deletions in 11 and 49% of their mitochondrial DNA, revealed a substantially lowered reserve capacity and increased flux control coefficient of COX, indicating severe rate limitations of oxidative phosphorylation by this enzyme.


Item Type:Article
Additional Information:Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc. Received for publication, June 5, 2000. Published, JBC Papers in Press, June 26, 2000, DOI 10.1074/jbc.M004833200 This work was supported by Deutsche Forschungsgemeinschaft Grant Ku 911/11-1, funds from the BONFOR Program of the University of Bonn, research grants of Aventis Pharma Germany and Deutsche Gesellschaft für Muskelkranke (to W.S.K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Subject Keywords:MITOCHONDRIAL DISEASES; IN-VIVO; ENCEPHALOMYOPATHIES; FIBERS; RESPIRATION; INHIBITOR; PHENOTYPE; MUTATION; GENOTYPE; CELL
Issue or Number:36
Record Number:CaltechAUTHORS:KUNjbc00
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:KUNjbc00
Alternative URL:http://dx.doi.org/10.1074/jbc.M004833200
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:5326
Collection:CaltechAUTHORS
Deposited By: Lindsay Cleary
Deposited On:10 Oct 2006
Last Modified:02 Oct 2019 23:21

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