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Assembly factors monitor sequential hemylation of cytochrome b to regulate mitochondria! translation
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
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2014 (English)In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 205, no 4, p. 511-524Article in journal (Refereed) Published
Abstract [en]

Mitochondrial respiratory chain complexes convert chemical energy into a membrane potential by connecting electron transport with charge separation. Electron transport relies on redox cofactors that occupy strategic positions in the complexes. How these redox cofactors are assembled into the complexes is not known. Cytochrome b, a central catalytic subunit of complex III, contains two henne bs. Here, we unravel the sequence of events in the mitochondrial inner membrane by which cytochrome b is hemylated. Heme incorporation occurs in a strict sequential process that involves interactions of the newly synthesized cytochrome b with assembly factors and structural complex III subunits. These interactions are functionally connected to cofactor acquisition that triggers the progression of cytochrome b through successive assembly intermediates. Failure to hemylate cytochrome b sequesters the Cbp3-Cbp6 complex in early assembly intermediates, thereby causing a reduction in cytochrome b synthesis via a feedback loop that senses hemylation of cytochrome b.

Place, publisher, year, edition, pages
2014. Vol. 205, no 4, p. 511-524
National Category
Cell Biology
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:su:diva-105918DOI: 10.1083/jcb.201401009ISI: 000336639000008OAI: oai:DiVA.org:su-105918DiVA, id: diva2:733258
Funder
Swedish Research CouncilCarl Tryggers foundation Knut and Alice Wallenberg FoundationNIH (National Institute of Health), GM101386
Note

AuthorCount:6;

Available from: 2014-07-08 Created: 2014-07-08 Last updated: 2020-04-27Bibliographically approved
In thesis
1. Biogenesis of the bc1 complex in mitochondria
Open this publication in new window or tab >>Biogenesis of the bc1 complex in mitochondria
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mitochondria perform a variety of tasks, but the function they are most prominent for is the energy conversion to form ATP, the universal energy equivalent of the cell. The majority of this ATP is created by the oxidative phosphorylation system, consisting of the respiratory chain and the ATP synthase. These elaborate machineries channel electrons through the respiratory complexes and thereby generate an electrochemical gradient across the inner mitochondrial membrane. This, so called proton motive force, is in turn utilized by the ATP Synthase to produce ATP.

A particularity of the oxidative phosphorylation complexes is that their subunits are derived from two genetic sources. As a result, and the fact that the respiratory chain complexes contain redox cofactors, the biogenesis of these enzymes is challenging and involves multiple, highly coordinated and regulated assembly steps. For the obligate homodimeric bc1 complex, a handful of assembly factors are known and its assembly can be divided into distinct assembly intermediates. In this work we provided insights into the maturation of the catalytic subunit cytochrome b. We revealed that the insertion of the redox active heme b groups is sequential and that it depends on the interaction with the early assembly factor Cbp4. With successful insertion of both heme bs, the binding of the structural subunit Qcr7 is necessary for stabilization and further assembly.

Furthermore, we were able to delineate the dimerization event in detail. We could establish that the interaction of the two matrix subunits, Cor1 and Cor2, with the bc1 complex assembly intermediate II, as well as the dissociation of Cbp4, are the triggering point for dimerization.

In our subsequent work we investigated the roles of the fairly uncharacterized assembly factor Bca1 and its interplay with the structural subunit Qcr7. We could demonstrate that Bca1 interacts early and transiently during assembly and is an important factor for efficient assembly. Additionally, we could show that Qcr7 is not only a structural subunit but also serves as an assembly checkpoint for the maturation of the bc1 complex.

With our work we could illustrate the necessity for basic biochemical research within the model organism yeast, as the fundamental molecular mechanisms are well conserved. This is exemplified by our work on UQCC3, the human orthologue of the bc1 complex assembly factor Cbp4.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry anb Biophysics, Stockholm University, 2020. p. 68
Keywords
Respiratory chain, bc1 complex assembly, mitochondrial protein biogenesis, molecular biology, yeast
National Category
Natural Sciences Biochemistry and Molecular Biology Chemical Sciences
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-180531 (URN)978-91-7911-116-8 (ISBN)978-91-7911-117-5 (ISBN)
Public defence
2020-06-11, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
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Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

Available from: 2020-05-18 Created: 2020-04-15 Last updated: 2020-05-26Bibliographically approved

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