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Impaired ATP synthase assembly associated with a mutation in the human ATP synthase subunit 6 gene

Nijtmans, Leo G. J. and Henderson, Nadine S. and Attardi, Giuseppe and Holti, Ian J. (2001) Impaired ATP synthase assembly associated with a mutation in the human ATP synthase subunit 6 gene. Journal of Biological Chemistry, 276 (9). pp. 6755-6762. ISSN 0021-9258. doi:10.1074/jbc.M008114200.

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Mutations in human mitochondrial DNA are a well recognized cause of disease. A mutation at nucleotide position 8993 of human mitochondrial DNA, located within the gene for ATP synthase subunit 6, is associated with the neurological muscle weakness, ataxia, and retinitis pigmentosa (NARP) syndrome. To enable analysis of this mutation in control nuclear backgrounds, two different cell lines were transformed with mitochondria carrying NARP mutant mitochondrial DNA. Transformant cell lines had decreased ATP synthesis capacity, and many also had abnormally high levels of two ATP synthase sub-complexes, one of which was F1-ATPase. A combination of metabolic labeling and immunoblotting experiments indicated that assembly of ATP synthase was slowed and that the assembled holoenzyme was unstable in cells carrying NARP mutant mitochondrial DNA compared with control cells. These findings indicate that altered assembly and stability of ATP synthase are underlying molecular defects associated with the NARP mutation in subunit 6 of ATP synthase, yet intrinsic enzyme activity is also compromised.

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Additional Information:© 2001 by The American Society for Biochemistry and Molecular Biology, Inc. Received for publication, September 5, 2000, and in revised form, October 26, 2000. This work was supported by the European Union in the form of a Training and Mobility of Researchers fellowship (to L.N.), the Scottish Hospital Endowments Research Trust, and the Medical Research Council.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. I. Holt and L. Nijtmans acknowledge debt to the late Dr. Coby Van den Bogert and the late Professor Anita Harding. We thank Professor H. T. Jacobs for comments on the manuscript and Dr. John Walker who kindly provided IF1 antibody. The abbreviations used are: mtDNA, mitochondrial DNA; NARP, neurological muscle weakness, ataxia, and retinitis pigmentosa; BN-PAGE, blue native-polyacrylamide gel electrophoresis; Bis- Tris, 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol; DMEM, Dulbecco's modified Eagle's medium; MOPS, 4-morpholinepropanesulfonic acid; OP, oxidative phosphorylation.
Issue or Number:9
Record Number:CaltechAUTHORS:NIJjbc01
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:3719
Deposited By: Lindsay Cleary
Deposited On:29 Jun 2006
Last Modified:08 Nov 2021 20:11

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