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Originally published In Press as doi:10.1074/jbc.M106363200 on July 30, 2001

J. Biol. Chem., Vol. 276, Issue 42, 38808-38813, October 19, 2001
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Lack of Complex I Activity in Human Cells Carrying a Mutation in MtDNA-encoded ND4 Subunit Is Corrected by the Saccharomyces cerevisiae NADH-Quinone Oxidoreductase (NDI1) Gene*

Yidong BaiDagger ||, Petr HájekDagger , Anne ChomynDagger , Elisa ChanDagger , Byoung Boo Seo§, Akemi Matsuno-Yagi§, Takao Yagi§, and Giuseppe AttardiDagger

From the Dagger  Division of Biology 156-29, California Institute of Technology, Pasadena, California 91125 and the § Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037

The gene for the single subunit, rotenone-insensitive, and flavone-sensitive internal NADH-quinone oxidoreductase of Saccharomyces cerevisiae (NDI1) can completely restore the NADH dehydrogenase activity in mutant human cells that lack the essential mitochondrial DNA (mtDNA)-encoded subunit ND4. In particular, the NDI1 gene was introduced into the nuclear genome of the human 143B.TK- cell line derivative C4T, which carries a homoplasmic frameshift mutation in the ND4 gene. Two transformants with a low or high level of expression of the exogenous gene were chosen for a detailed analysis. In these cells the corresponding protein is localized in mitochondria, its NADH-binding site faces the matrix compartment as in yeast mitochondria, and in perfect correlation with its abundance restores partially or fully NADH-dependent respiration that is rotenone-insensitive, flavone-sensitive, and antimycin A-sensitive. Thus the yeast enzyme has become coupled to the downstream portion of the human respiratory chain. Furthermore, the P:O ratio with malate/glutamate-dependent respiration in the transformants is approximately two-thirds of that of the wild-type 143B.TK- cells, as expected from the lack of proton pumping activity in the yeast enzyme. Finally, whereas the original mutant cell line C4T fails to grow in medium containing galactose instead of glucose, the high NDI1-expressing transformant has a fully restored capacity to grow in galactose medium. The present observations substantially expand the potential of the yeast NDI1 gene for the therapy of mitochondrial diseases involving complex I deficiency.

* This work was supported by National Institutes of Health Grant GM 11726 (to G. A.) and Grant RO1 DK 53244 (to M.-Y. and T. Y.).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.

|| Present address: Dept. Cell. Struct. Biology, University of Texas HSC, San Antonio, TX 78229-3900.

To whom correspondence should be addressed. Tel.: 626-395-4930; Fax: 626-449-0756; E-mail: attardi@caltech.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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