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Molecular and Cellular Biology, October 1998, p. 5868-5879, Vol. 18, No. 10
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

The Deafness-Associated Mitochondrial DNA Mutation at Position 7445, Which Affects tRNASer(UCN) Precursor Processing, Has Long-Range Effects on NADH Dehydrogenase Subunit ND6 Gene Expression

Min-Xin Guan,1 José Antonio Enriquez,1,dagger Nathan Fischel-Ghodsian,2 Ram S. Puranam,1,Dagger Catherine P. Lin,1 Marion A. Maw,3 and Giuseppe Attardi1,*

Division of Biology, California Institute of Technology, Pasadena, California 911251; Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research Center, Cedars-Sinai Medical Center, Los Angeles, California 900482; and Department of Biochemistry, University of Otago, Dunedin, New Zealand3

Received 30 April 1998/Accepted 11 July 1998

The pathogenetic mechanism of the deafness-associated mitochondrial DNA (mtDNA) T7445C mutation has been investigated in several lymphoblastoid cell lines from members of a New Zealand pedigree exhibiting the mutation in homoplasmic form and from control individuals. We show here that the mutation flanks the 3' end of the tRNASer(UCN) gene sequence and affects the rate but not the sites of processing of the tRNA precursor. This causes an average reduction of ~70% in the tRNASer(UCN) level and a decrease of ~45% in protein synthesis rate in the cell lines analyzed. The data show a sharp threshold in the capacity of tRNASer(UCN) to support the wild-type protein synthesis rate, which corresponds to ~40% of the control level of this tRNA. Strikingly, a 7445 mutation-associated marked reduction has been observed in the level of the mRNA for the NADH dehydrogenase (complex I) ND6 subunit gene, which is located ~7 kbp upstream and is cotranscribed with the tRNASer(UCN) gene, with strong evidence pointing to a mechanistic link with the tRNA precursor processing defect. Such reduction significantly affects the rate of synthesis of the ND6 subunit and plays a determinant role in the deafness-associated respiratory phenotype of the mutant cell lines. In particular, it accounts for their specific, very significant decrease in glutamate- or malate-dependent O2 consumption. Furthermore, several homoplasmic mtDNA mutations affecting subunits of NADH dehydrogenase may play a synergistic role in the establishment of the respiratory phenotype of the mutant cells.

* Corresponding author. Mailing address: Division of Biology, California Institute of Technology, Pasadena, CA 91125. Phone: (626) 395-4930. Fax: (626) 449-0756. E-mail: attardig{at}seqaxp.bio.caltech.edu.

dagger Present address: Departamento de Bioquímica, Universidad de Zaragoza, 50013 Zaragoza, Spain.

Dagger Present address: Department of Medicine, Duke University Medical Center, Durham, NC 27710.

Molecular and Cellular Biology, October 1998, p. 5868-5879, Vol. 18, No. 10
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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