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A pathogenic mutation in cytochrome c oxidase results in impaired proton pumping while retaining O-2-reduction activity
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
2010 (English)In: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1797, no 5, 550-556 p.Article in journal (Refereed) Published
Abstract [en]

In this work we have investigated the effect of a pathogenic mitochondrial DNA mutation found in human colon cells, at a functional-molecular level. The mutation results in the amino-acid substitution Tyr19His in subunit I of the human CytcO and it is associated with respiratory deficiency. It was introduced into Rhodobacter sphaeroides, which carries a cytochrome c oxidase (cytochrome aa(3)) that serves as a model of the mitochondrial counterpart. The residue is situated in the middle of a pathway that is used to transfer substrate protons as well as protons that are pumped across the membrane. The Tyr33His (equivalent residue in the bacterial CytcO) structural variant of the enzyme was purified and its function was investigated. The results show that in the structurally altered CytcO the activity decreased due to slowed proton transfer; proton transfer from an internal proton donor, the highly-conserved Glu286, to the catalytic site was slowed by a factor of similar to 5, while reprotonation of the Glu from solution was slowed by a factor of similar to 40. In addition, in the structural variant proton pumping was completely impaired. These results are explained in terms of introduction of a barrier for proton transfer through the D pathway and changes in the coordination of water molecules surrounding the Glu286 residue. The study offers an explanation, at the molecular level, to the link between a specific amino-acid substitution and a pathogenic phenotype identified in human colon cells. 

Place, publisher, year, edition, pages
2010. Vol. 1797, no 5, 550-556 p.
Keyword [en]
Respiratory chain, Electron transfer, Mitochondrial disease, Cytochrome aa(3), Mitochondria, Deficiency, mtDNA
National Category
Biological Sciences
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:su:diva-50683DOI: 10.1016/j.bbabio.2010.01.027ISI: 000276621100004OAI: oai:DiVA.org:su-50683DiVA: diva2:382300
Note
authorCount :4Available from: 2010-12-30 Created: 2010-12-30 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Cytochrome c Oxidase dysfunction in cancer: Exploring the molecular mechanisms
Open this publication in new window or tab >>Cytochrome c Oxidase dysfunction in cancer: Exploring the molecular mechanisms
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mutations in genes encoding the mitochondrial enzyme Cytochrome c Oxidase (CytcO) have lately been found in connection to various types of cancer. Some mutations result in substitutions of highly conserved amino-acid residues. As CytcO is an essential enzyme in oxidative phosphorylation, the substitutions are likely to have deleterious effects on the cellular energy metabolism. There is, however, a lack of data on the functional consequences of the pathogenic substitutions. In the publications on which this thesis is based, we investigated the effects of the substitutions on a molecular level. This was done using the validated bacterial model organism Rhodobacter sphaeroides which has a CytcO that is both structurally and functionally similar to the mammalian CytcO. For the functional studies, we used spectroscopic techniques to investigate the overall activity of the enzyme as well as the proton-pumping efficiency and the internal proton and electron transfers. We found that most of the CytcO substitutions observed in connection to cancer, resulted in a decreased catalytic activity. The impaired activity was due to defects in specific electron- or proton-transfer processes. Moreover, in several cases the substitutions resulted in an impaired proton-pumping activity. This thesis deals with the relevance of using R. sphaeroides CytcO as a model system for investigating human disease, as well as the possible links between the defective enzyme and the development of cancer.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2012. 65 p.
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-65303 (URN)978-91-7447-424-4 (ISBN)
Public defence
2012-02-03, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Available from: 2012-01-12 Created: 2011-12-06 Last updated: 2012-01-05Bibliographically approved

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