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In vivo control of respiration by cytochrome c oxidase in wild-type and mitochondrial DNA mutation-carrying human cells

Villani, Gaetano and Attardi, Giuseppe (1997) In vivo control of respiration by cytochrome c oxidase in wild-type and mitochondrial DNA mutation-carrying human cells. Proceedings of the National Academy of Sciences of the United States of America, 94 (4). pp. 1166-1171. ISSN 0027-8424. PMCID PMC19762.

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The metabolic control of respiration is still poorly understood, due mainly to the lack of suitable approaches for studying it in vivo. Experiments on isolated mammalian mitochondria have indicated that a relatively small fraction of each of several components of the electron transport chain is sufficient to sustain a normal O-2 consumption rate. These experiments, however, may not reflect accurately the in vivo situation, due to the lack in the mitochondrial fraction of essential cytosolic components and to the use of excess of substrates in the in vitro assays. An approach is described here whereby the control of respiration by cytochrome c oxidase (COX; EC was analyzed in intact cultured human osteosarcoma 143B.TK- cells and other wild-type cells and in mitochondrial DNA mutation-carrying human cell lines. Surprisingly, in wild-type cells, only a slightly higher COX capacity mas detected than required to support the endogenous respiration rate, pointing to a tighter in vivo control of respiration by COX than generally assumed. Cell lines carrying the MERRF mitochondrial tRNA(Lys) gene mutation, which causes a pronounced decrease in mitochondrial protein synthesis and respiration rates, revealed, in comparison, a significantly greater COX capacity relative to the residual endogenous respiration rate, and, correspondingly, a higher COX inhibition threshold above which the overall respiratory flux was affected. The observed relationship between COX respiratory threshold and relative COX capacity and the potential extension of the present analysis to other respiratory complexes have significant general implications for understanding the pathogenetic role of mutations in mtDNA-linked diseases and the tissue specificity of the mutation-associated phenotype.

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Additional Information:© 1997 by the National Academy of Sciences. Contributed by Giuseppe Attardi, December 16, 1996. G.V. thanks Dr. N. Capitanio for helpful discussions, advice, and encouragement throughout the project. We are also very grateful to Drs. Y. Hatefi, S. Papa, and A. Chomyn for their critical reading of the manuscript and their valuable comments, to Drs. J. A. Enriquez and J. Cabezas for their help in the primer extensions experiments, and to B. Keeley, A. Drew, and R. Zedan for technical assistance. These investigations were supported by National Institutes of Health Grant GM-11726 to G.A. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Subject Keywords:flux control, N,N,N',N'-tetramethyl-p-phenylenediamine, polarography, MERRF mutation, rat muscle, complementation, MERRF, MTDNA
Issue or Number:4
PubMed Central ID:PMC19762
Record Number:CaltechAUTHORS:VILpnas97
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:1190
Deposited By: Tony Diaz
Deposited On:04 Jan 2006
Last Modified:02 Oct 2019 22:40

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