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A mitochondrial DNA mutation linked to colon cancer results in proton leaks in cytochrome c oxidase
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
2009 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 9, 3402-3407 p.Article in journal (Refereed) Published
Abstract [en]

An increasing number of cancer types have been found to be linked to specific mutations in the mitochondrial DNA, which result in specific structural changes of the respiratory enzyme complexes. In this study, we have investigated the effect of 2 such mutations identified in colon cancer patients, leading to the amino acid substitutions Ser458Pro and Gly125Asp in subunit I of cytochrome c oxidase (complex IV) [Greaves et al. (2006) Proc Natl Acad Sci USA 103:714-719]. We introduced these mutations in Rhodobacter sphaeroides, which carries an oxidase that serves as a model of the mitochondrial counterpart. The lack of expression of the former variant indicates that the amino acid substitution results in severely altered overall structure of the enzyme. The latter mutation (Gly171Asp in the bacterial oxidase) resulted in a structurally intact enzyme, but with reduced activity (approximately 30%), mainly due to slowed reduction of the redox site heme a. Furthermore, even though the Gly171Asp CytcO pumps protons, an intrinsic proton leak was identified, which would lead to a decreased overall energy-conversion efficiency of the respiratory chain, and would also perturb transport processes such as protein, ion, and metabolite trafficking. Furthermore, the specific leak may act to alter the balance between the electrical and chemical components of the proton electrochemical gradient.

Place, publisher, year, edition, pages
2009. Vol. 106, no 9, 3402-3407 p.
National Category
Biological Sciences
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:su:diva-34712DOI: 10.1073/pnas.0811450106ISI: 000263844100076PubMedID: 19218458OAI: oai:DiVA.org:su-34712DiVA: diva2:285335
Available from: 2010-01-11 Created: 2010-01-11 Last updated: 2017-12-12Bibliographically 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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