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Molecular and Cellular Biology, November 2002, p. 7614-7621, Vol. 22, No. 21
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.21.7614-7621.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Mammalian Copper Chaperone Cox17p Has an Essential Role in Activation of Cytochrome c Oxidase and Embryonic Development

Yoshinori Takahashi,1 Koichiro Kako,1* Shin-ichi Kashiwabara,1 Akio Takehara,1 Yoshiko Inada,1 Hidenori Arai,1 Kazuto Nakada,2 Hiroko Kodama,3 Jun-ichi Hayashi,2 Tadashi Baba,1 and Eisuke Munekata1

Institute of Applied Biochemistry,1 Institute of Biological Sciences University of Tsukuba, Tsukuba 305-8572,2 Department of Pediatrics, Teikyo University School of Medicine, Tokyo 173-8605, Japan3

Received 19 April 2002/ Returned for modification 29 May 2002/ Accepted 9 July 2002

Cox17p is essential for the assembly of functional cytochrome c oxidase (CCO) and for delivery of copper ions to the mitochondrion for insertion into the enzyme in yeast. Although this small protein has already been cloned or purified from humans, mice, and pigs, the function of Cox17p in the mammalian system has not yet been elucidated. In vitro biochemical data for mammalian Cox17p indicate that the copper binds to the sequence -KPCCAC-. Although mouse embryos homozygous for COX17 disruption die between embryonic days E8.5 and E10, they develop normally until E6.5. This phenotype is strikingly similar to embryos of Ctr1(-/-), a cell surface copper transporter, in its lethality around the time of gastrulation. COX17-deficient embryos exhibit severe reductions in CCO activity at E6.5. Succinate dehydrogenase activity and immunoreactivities for anti-COX subunit antibodies were normal in the COX17(-/-) embryos, indicating that this defect was not caused by the deficiency of other complexes and/or subunits but was caused by impaired CCO activation by Cox17p. Since other copper chaperone (Atox1 and CCS)-deficient mice show a more moderate defect, the disruption of the COX17 locus causes the expression of only the phenotype of Ctr1(-/-). We found that the activity of lactate dehydrogenase was also normal in E6.5 embryos, implying that the activation of CCO by Cox17p may not be essential to the progress of embryogenesis before gastrulation.

* Corresponding author. Mailing address: Institute of Applied Biochemistry, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan. Phone: 81-298-53-7205. Fax: 81-298-53-4605. E-mail: JAB03176{at}nifty.ne.jp.

Molecular and Cellular Biology, November 2002, p. 7614-7621, Vol. 22, No. 21
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.21.7614-7621.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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