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J Biol Chem, Vol. 275, Issue 18, 13994-14003, May 5, 2000
From the A 15-base pair, in-frame, deletion
(9480del15) in the mitochondrial DNA (mtDNA)-encoded cytochrome
c oxidase subunit III (COX III) gene was identified
previously in a patient with recurrent episodes of myoglobinuria and an
isolated COX deficiency. Transmitochondrial cell lines harboring 0, 97, and 100% of the 9480del15 deletion were created by fusing human cells
lacking mtDNA (
A Pathogenic 15-Base Pair Deletion in Mitochondrial DNA-encoded
Cytochrome c Oxidase Subunit III Results in the Absence of
Functional Cytochrome c Oxidase*
§,, and
Department of Molecular and Medical
Genetics, Oregon Health Sciences University, Portland, Oregon 97201, the ¶ Department of Neurology, College of Physicians and Surgeons,
Columbia University, New York, New York 10032, and the
§ Department of Biochemistry and Molecular Pharmacology,
Thomas Jefferson University, Philadelphia, Pennsylvania 19107
0 cells) with platelet and lymphocyte
fractions isolated from the patient. The COX III gene mutation resulted
in a severe respiratory chain defect in all mutant cell lines. Cells
homoplasmic for the mutation had no detectable COX activity or
respiratory ATP synthesis, and required uridine and pyruvate
supplementation for growth, a phenotype similar to 0
cells. The cells with 97% mutated mtDNA exhibited severe reductions in
both COX activity (6% of wild-type levels) and rates of ATP synthesis
(9% of wild-type). The COX III polypeptide in the mutant cells,
although translated at rates similar to wild-type, had reduced
stability. There was no evidence for assembly of COX I, COX II, or COX
III subunits in a multisubunit complex in cells homoplasmic for the
mutation, thus indicating that there was no stable assembly of COX I
with COX II in the absence of wild-type COX III. In contrast, the COX I
and COX II subunits were assembled in cells with 97% mutated
mtDNA.
*
This work was supported by grants from the National
Institutes of Health and the Muscular Dystrophy Association.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.
To whom correspondence should be addressed: Dept. of
Biochemistry and Molecular Pharmacology, 308 BLSB, Thomas Jefferson
University, 233 S. 10th St., Philadelphia, PA 19107. Tel.:
215-503-4845; Fax: 215-503-5393; E-mail:
Michael.King@mail.tju.edu.
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