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Biogenesis of the Bc1 Complex in Mitochondria

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Biogenesis of the Bc1 Complex in Mitochondria Katharina Stephan Biogenesis of the bc1 complex in mitochondria Katharina Stephan Biogenesis of the Biogenesis of bc 1 complex in mitochondria Katharina Stephan ISBN 978-91-7911-116-8 Department of Biochemistry and Biophysics Doctoral Thesis in Biochemistry at Stockholm University, Sweden 2020 Biogenesis of the bc1 complex in mitochondria Katharina Stephan Academic dissertation for the Degree of Doctor of Philosophy in Biochemistry at Stockholm University to be publicly defended on Thursday 11 June 2020 at 10.00 in Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B. Abstract 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. Keywords: Respiratory chain, bc1 complex assembly, mitochondrial protein biogenesis, molecular biology, yeast. Stockholm 2020 http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-180531 ISBN 978-91-7911-116-8 ISBN 978-91-7911-117-5 Department of Biochemistry and Biophysics Stockholm University, 106 91 Stockholm BIOGENESIS OF THE BC1 COMPLEX IN MITOCHONDRIA Katharina Stephan Biogenesis of the bc1 complex in mitochondria Katharina Stephan ©Katharina Stephan, Stockholm University 2020 ISBN print 978-91-7911-116-8 ISBN PDF 978-91-7911-117-5 Printed in Sweden by Universitetsservice US-AB, Stockholm 2020 List of publications I. Hildenbeutel M, Hegg EL, Stephan K, Gruschke S, Meunier B, Ott M. Assembly factors monitor sequential hemylation of cyto- chrome b to regulate mitochondrial translation. (2014) J Cell Biol. 205(4):511-24. II. Stephan K and Ott M. Timing of dimerization of the bc1 complex during mitochondrial respiratory chain assembly. (2020) Biochim Biophys Acta Bioenerg. 1861(5-6):148177. III. Wanschers BF, Szklarczyk R, van den Brand MA, Jonckheere A, Suijskens J, Smeets R, Rodenburg RJ, Stephan K, Helland IB, Elkamil A, Rootwelt T, Ott M, van den Heuvel L, Nijtmans LG, Huynen MA. A mutation in the human CBP4 ortholog UQCC3 impairs Complex III assembly, activity and cytochrome b stabil- ity. (2014) Hum Mol Genet. (23):6356-65. IV. Stephan K, Singh AP, Römpler K, Hildenbeutel M, Meunier B, Ott M. Role of Bca1 and the early structural subunit Qcr7 in bc1 com- plex biogenesis. Manuscript Additional publications I. Möller-Hergt BV, Carlström A, Stephan K, Imhof A, Ott M. The ribosome receptors Mrx15 and Mba1 jointly organize cotransla- tional insertion and protein biogenesis in mitochondria (2018) Mol Biol Cell. (20):2386-2396. Abbreviations ATP adenosine triphosphate OXPHOS oxidative phosphorylation CII – CIV complex II – IV of the respiratory chain FAD/FADH2 flavin adenine dinucleotide NAD+/NADH nicotinamide adenine dinucleotide FeS iron-sulfur cluster IMM inner mitochondrial membrane IMS intermembrane space Q/QH2 ubiquinone/ubiquinol ROS reactive oxygen species SC supercomplex TM transmembrane COB cytochrome b (gene and mRNA) MRP mitochondrial ribosomal protein OMM outer mitochondrial membrane mitoribosome mitochondrial ribosome mtDNA mitochondrial DNA UTR untranslated region Cryo EM cryo electron microscopy pmf proton motive force Contents List of publications .................................................................................... i Additional publications ..............................................................................ii Abbreviations .......................................................................................... iii Introduction ............................................................................................. 1 Mitochondria ............................................................................................................ 1 Oxidative phosphorylation......................................................................................... 4 The mitochondrial F1Fo-ATP Synthase ................................................................. 4 Respiratory chain complexes .................................................................................... 6 Complex I ........................................................................................................... 8 NADH dehydrogenases in yeast ........................................................................ 11 Complex II......................................................................................................... 12 Complex III........................................................................................................ 15 Complex IV ....................................................................................................... 21 Supercomplexes .................................................................................................... 25 Functional significance ...................................................................................... 25 Dual genetic origin.................................................................................................. 27 Why mitochondria keep their own genome ......................................................... 28 Mitochondrial translation ......................................................................................... 29 Synthesis of Cytochrome b ................................................................................ 31 Complex III assembly ............................................................................................. 33 Assembly factors of the bc1 complex .................................................................. 33 The assembly line of the bc1 complex................................................................. 37 Aim of this thesis ................................................................................... 39 Summary of the papers .......................................................................................... 39 Paper I: ............................................................................................................. 39 Paper II: ............................................................................................................ 40 Paper III: ........................................................................................................... 41 Paper IV:........................................................................................................... 42 Conclusion and remarks ......................................................................................... 43 Populärwissenschaftliche Zusammenfassung.......................................... 45 Populärvetenskaplig sammanfattning...................................................... 47 Acknowledgments ................................................................................. 48 References ........................................................................................... 51 Introduction Mitochondria Mitochondria are organelles within eukaryotic cells that fulfill a plei- otropic variety of tasks and belong to the most studied organelles of the cell. Mitochondria are very dynamic and variable, they are able to form a network and can adapt to the needs of their cell. For example, the number of mitochondria in a cell of the baker’s yeast Saccharomyces cerevisiae depend on the growth conditions, or mammalian cells can have up to 104 mitochondria depending on the energy
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