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  • 1.
    Gruschke, Steffi
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Early steps in the biogenesis of the bc1 complex in yeast mitochondria: The role of the Cbp3-Cbp6 complex in cytochrome b synthesis and assembly2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The inner membrane of mitochondria harbors the complexes of the respiratory chain and the ATP synthase, which perform the key metabolic process oxidative phosphorylation. These complexes are composed of subunits from two different genetic origins: the majority of constituents is synthesized on cytosolic ribosomes and imported into mitochondria, but a handful of proteins, which represent core catalytic subunits, are encoded in the organellar DNA and translated on mitochondrial ribosomes. Using yeast as a model organism, I investigated the mitochondrial ribosomal tunnel exit, the region of the ribosome where the nascent chain emerges and that in cytosolic ribosomes serves as a platform to bind biogenesis factors that help the newly synthesized protein to mature. This study provided insights into the structural composition of this important site of mitochondrial ribosomes and revealed the positioning of Cbp3 at the tunnel exit region, a chaperone required specifically for the assembly of the bc1 complex. In my further work I found that Cbp3 structurally and functionally forms a tight complex with Cbp6 and that this complex exhibits fundamental roles in the biogenesis of cytochrome b, the mitochondrially encoded subunit of the bc1 complex. Bound to the ribosome, Cbp3-Cbp6 stimulates translation of the cytochrome b mRNA (COB mRNA). Cbp3-Cbp6 then binds the fully synthesized cytochrome b, thereby stabilizing and guiding it further through bc1 complex assembly. The next steps involve the recruitment of the assembly factor Cbp4 to the Cbp3-Cbp6/cytochrome b complex and presumably acquisition of two redox active heme b cofactors. During further assembly Cbp3-Cbp6 is released from cytochrome b, can again bind to the ribosome and activate further rounds of COB mRNA translation. The dual role of Cbp3-Cbp6 in both translation and assembly allows the complex to act as a regulatory switch to modulate the level of cytochrome b synthesis in response to the bc1 complex assembly process.

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  • 2.
    Gruschke, Steffi
    et al.
    Technische Universität Kaiserslautern, Germany.
    Groene, Kerstin
    Heublein, Manfred
    Technische Universität Kaiserslautern, Germany.
    Hoelz, Stefanie
    Israel, Lars
    Imhof, Axel
    Herrmann, Johannes M.
    Ott, Martin
    Proteins at the Polypeptide Tunnel Exit of the Yeast Mitochondrial Ribosome2010In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 285, no 25, p. 19022-19028Article in journal (Refereed)
    Abstract [en]

    Oxidative phosphorylation in mitochondria requires the synthesis of proteins encoded in the mitochondrial DNA. The mitochondrial translation machinery differs significantly from that of the bacterial ancestor of the organelle. This is especially evident from many mitochondria-specific ribosomal proteins. An important site of the ribosome is the polypeptide tunnel exit. Here, nascent chains are exposed to an aqueous environment for the first time. Many biogenesis factors interact with the tunnel exit of pro- and eukaryotic ribosomes to help the newly synthesized proteins to mature. To date, nothing is known about the organization of the tunnel exit of mitochondrial ribosomes. We therefore undertook a comprehensive approach to determine the composition of the yeast mitochondrial ribosomal tunnel exit. Mitochondria contain homologues of the ribosomal proteins located at this site in bacterial ribosomes. Here, we identified proteins located in their proximity by chemical cross-linking and mass spectrometry. Our analysis revealed a complex network of interacting proteins including proteins and protein domains specific to mitochondrial ribosomes. This network includes Mba1, the membrane-bound ribosome receptor of the inner membrane, as well as Mrpl3, Mrpl13, and Mrpl27, which constitute ribosomal proteins exclusively found in mitochondria. This unique architecture of the tunnel exit is presumably an adaptation of the translation system to the specific requirements of the organelle.

  • 3.
    Gruschke, Steffi
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Kehrein, Kirsten
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Roempler, Katharina
    Groene, Kerstin
    Israel, Lars
    Imhof, Axel
    Herrmann, Johannes M.
    Ott, Martin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Cbp3-Cbp6 interacts with the yeast mitochondrial ribosomal tunnel exit and promotes cytochrome b synthesis and assembly2011In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 193, no 6, p. 1101-1114Article in journal (Refereed)
    Abstract [en]

    Mitochondria contain their own genetic system to express a small number of hydrophobic polypeptides, including cytochrome b, an essential subunit of the bc(1) complex of the respiratory chain. In this paper, we show in yeast that Cbp3, a bc(1) complex assembly factor, and Cbp6, a regulator of cytochrome b translation, form a complex that associates with the polypeptide tunnel exit of mitochondrial ribosomes and that exhibits two important functions in the biogenesis of cytochrome b. On the one hand, the interaction of Cbp3 and Cbp6 with mitochondrial ribosomes is necessary for efficient translation of cytochrome b messenger ribonucleic acid or transcript. On the other hand, the Cbp3-Cbp6 complex interacts directly with newly synthesized cytochrome b in an assembly intermediate that is not ribosome bound and that contains the assembly factor Cbp4. Our results suggest that synthesis of cytochrome b occurs preferentially on those ribosomes that have the Cbp3-Cbp6 complex bound to their tunnel exit, an arrangement that may ensure tight coordination of cytochrome b synthesis and assembly.

  • 4.
    Gruschke, Steffi
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Römpler, Katharina
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hildenbeutel, Markus
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Kehrein, Kirsten
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Kuehl, Inge
    Bonnefoy, Nathalie
    Ott, Martin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    The Cbp3-Cbp6 complex coordinates cytochrome b synthesis with bc(1) complex assembly in yeast mitochondria2012In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 199, no 1, p. 137-150Article in journal (Refereed)
    Abstract [en]

    Respiratory chain complexes in mitochondria are assembled from subunits derived from two genetic systems. For example, the bc1 complex consists of nine nuclear encoded subunits and the mitochondrially encoded subunit cytochrome b. We recently showed that the Cbp3-Cbp6 complex has a dual function for biogenesis of cytochrome b: it is both required for efficient synthesis of cytochrome b and for protection of the newly synthesized protein from proteolysis. Here, we report that Cbp3-Cbp6 also coordinates cytochrome b synthesis with bc1 complex assembly. We show that newly synthesized cytochrome b assembled through a series of four assembly intermediates. Blocking assembly at early and intermediate steps resulted in sequestration of Cbp3-Cbp6 in a cytochrome b-containing complex, thereby making Cbp3-Cbp6 unavailable for cytochrome b synthesis and thus reducing overall cytochrome b levels. This feedback loop regulates protein synthesis at the inner mitochondrial membrane by directly monitoring the efficiency of bc1 complex assembly.

  • 5.
    Hildenbeutel, Markus
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hegg, Eric L.
    Gruschke, Steffi
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Meunier, Brigitte
    Ott, Martin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    The timing of heme incorporation into yeast cytochrome bManuscript (preprint) (Other academic)
    Abstract [en]

    During oxidative phosphorylation electrons are transferred from NADH and succinate to the final electron acceptor oxygen by the complexes of the respiratory chain. These complexes carry redox active prosthetic groups that allow the transfer of electrons. Cytochrome b of the bc1 complex is encoded in the mitochondrial genome and acquires two heme b cofactors during its biogenesis. In this work we aimed to understand the mechanism and timing of cytochrome b hemylation. We provide evidence that cytochrome b present in the first bc1 complex assembly intermediate that contains the assembly factors Cbp3-Cbp6 and Cbp4 carries heme. This demonstrates that heme acquisition occurs very early during cytochrome b biogenesis. Moreover, by analyzing cytochrome b mutants lacking either of the two heme moieties, we reveal an obligate order of heme insertion into cytochrome b and suggest an incorporation mode from the intermembrane space. We propose a model in which Cbp3-Cbp6 keeps cytochrome b in a conformation allowing heme acquisition. Upon heme insertion, cytochrome b most likely undergoes a conformational change that enables binding of Cbp4, a pre-requisite for further assembly. Cbp4 thus might exhibit a proofreading function in hemylation.

  • 6.
    Hildenbeutel, Markus
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hegg, Eric L.
    Stephan, Katharina
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gruschke, Steffi
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Meunier, Brigitte
    Ott, Martin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Assembly factors monitor sequential hemylation of cytochrome b to regulate mitochondria! translation2014In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 205, no 4, p. 511-524Article in journal (Refereed)
    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.

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