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Mitochondrial biogenesis in Trypanosoma brucei - Expect the unexpected

English title Mitochondrial biogenesis in Trypanosoma brucei - Expect the unexpected
Applicant Schneider André
Number 175563
Funding scheme Project funding (Div. I-III)
Research institution Departement für Chemie und Biochemie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Biochemistry
Start/End 01.01.2018 - 31.12.2021
Approved amount 1'224'000.00
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Keywords (6)

mitochondrial genome inheritance; mitochondria; mitochondrial cristae formation; outer mitochondrial membrane; trypanosoma; mitochondrial protein import

Lay Summary (German)

Lead
Wie entstehen Mitochondrien und welche Rolle haben sie bei der Entstehung von komplexen Zellen gespielt? In diesem Forschungsprojekt wird der einzellige Parasit Trypanosoma brucei als Modellsystem gebraucht um diese Fragen zu studieren. Sein mitochondrielles Proteinimportsystem ist dabei von besonderem Interesse, da es ganz anders aufgebaut ist als in anderen komplexen Zellen. Eine vergleichende Analyse verschiedener Proteinimportsysteme könnte es deshalb erlauben Rückschlüsse zu ziehen, wie die ersten komplexen Zellen enstanden sein könnten.
Lay summary

Alle komplexen Zellen haben abgetrennte Kompartimente, welche Organellen genannt werden. Die wohl wichtigsten Organellen sind der Zellkern und das Mitochondrium, welches als Kraftwerk dient. Vieles deutet darauf hin, dass die Mitochondrien die ältesten Organellen sind. Die Entstehung der Mitochondrien war also, neben der Entstehung der ersten Zelle überhaupt, das wohl wichtigste Ereignis in der Geschichte des Lebens.

Wir wissen, dass vor etwa zwei Milliarden Jahren eine einfache Zelle ein Bakterium in sich aufgenommen hat aus dem dann das Mitochondrium entstanden ist. Dazu mussten Importsysteme entwickelt werden, die es der neu entstandenen Organelle erlaubten Stoffe von der "Wirtszelle" aufzunehmen. Das Importsystem für Proteine ist hier von besonderem Interesse, denn Proteine sind schwierig zu transportieren. Dank Forschungen mit Hefe und mit Säugerzellen wissen wir heute, wie die Protein Import-Maschinerien von Mitochondrien aussehen und wie sie auf molekularer Ebene funktionieren.

Forschungen in unserem Labor haben jedoch gezeigt, dass die entsprechenden mitochondriellen Protein-Importsysteme von Trypanosomen grosse, zum Teil fundamentale Unterschiede zu den entsprechenden Systemen von Hefe und Säugern aufweisen. Ein Ziel unserer Forschungen ist es deshalb die trypanosomalen Import-Systeme funktionell zu charakterisieren um die generellen, grundlegenden Prinzipien des Proteinimportes zu verstehen. Zudem sollte es ein Vergleich der Gemeinsamkeiten und Unterschiede der verschiedenen Systemen erlauben zu rekonstruieren wie die ursprüngliche Proteinimportmaschinerie im Urahne aller eukaryontischen Zellen ausgesehen haben könnte. Diese Erkenntnisse wiederum werden helfen Szenarien zu fomulieren, wie der ursprüngliche bakterielle Endosymbiont in das Mitochondrium konvertiert wurde.

Direct link to Lay Summary Last update: 27.11.2017

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Publications

Publication
Structural Insights into the Mechanism of Mitoribosomal Large Subunit Biogenesis
Jaskolowski Mateusz, Ramrath David J.F., Bieri Philipp, Niemann Moritz, Mattei Simone, Calderaro Salvatore, Leibundgut Marc, Horn Elke K., Boehringer Daniel, Schneider André, Ban Nenad (2020), Structural Insights into the Mechanism of Mitoribosomal Large Subunit Biogenesis, in Molecular Cell, 79, 1-16.
Evolution of mitochondrial protein import – lessons from trypanosomes
Schneider André (2020), Evolution of mitochondrial protein import – lessons from trypanosomes, in Biological Chemistry, 401(6-7), 663-676.
The single CCA-adding enzyme of T. brucei has distinct functions in the cytosol and in mitochondria
Shikha Shikha, Schneider André (2020), The single CCA-adding enzyme of T. brucei has distinct functions in the cytosol and in mitochondria, in Journal of Biological Chemistry, 295(18), 6138-6150.
Lexis and Grammar of Mitochondrial RNA Processing in Trypanosomes
Aphasizheva Inna, Alfonzo Juan, Carnes Jason, Cestari Igor, Cruz-Reyes Jorge, Göringer H. Ulrich, Hajduk Stephen, Lukeš Julius, Madison-Antenucci Susan, Maslov Dmitri A., McDermott Suzanne M., Ochsenreiter Torsten, Read Laurie K., Salavati Reza, Schnaufer Achim, Schneider André, Simpson Larry, Stuart Kenneth, Yurchenko Vyacheslav, Zhou Z. Hong, Zíková Alena, Zhang Liye, Zimmer Sara, Aphasizhev Ruslan (2020), Lexis and Grammar of Mitochondrial RNA Processing in Trypanosomes, in Trends in Parasitology, 36(4), 337-355.
A Scalable Purification Method for Mitochondria from Trypanosoma brucei
Niemann Moritz, Schneider André (2020), A Scalable Purification Method for Mitochondria from Trypanosoma brucei, Springer US, New York, NY, 611-626.
Homologue replacement in the import motor of the mitochondrial inner membrane of trypanosomes
von Känel Corinne, Muñoz-Gómez Sergio A, Oeljeklaus Silke, Wenger Christoph, Warscheid Bettina, Wideman Jeremy G, Harsman Anke, Schneider Andre (2020), Homologue replacement in the import motor of the mitochondrial inner membrane of trypanosomes, in eLife, 9, 0-0.
Inducible orthogonal aminoacylation demonstrates that charging is required for mitochondrial tRNA import in Trypanosoma brucei
Huot Jonathan L., Shikha Shikha, Schneider André (2019), Inducible orthogonal aminoacylation demonstrates that charging is required for mitochondrial tRNA import in Trypanosoma brucei, in Scientific Reports, 9(1), 10836-10836.
A tRNA half modulates translation as stress response in Trypanosoma brucei
Fricker Roger, Brogli Rebecca, Luidalepp Hannes, Wyss Leander, Fasnacht Michel, Joss Oliver, Zywicki Marek, Helm Mark, Schneider André, Cristodero Marina, Polacek Norbert (2019), A tRNA half modulates translation as stress response in Trypanosoma brucei, in Nature Communications, 10(1), 118-118.
The highly diverged trypanosomal MICOS complex is organized in a non‐essential integral membrane and an essential peripheral module
Eichenberger Claudia, Oeljeklaus Silke, Bruggisser Julia, Mani Jan, Haenni Beat, Kaurov Iosif, Niemann Moritz, Zuber Benoît, Lukeš Julius, Hashimi Hassan, Warscheid Bettina, Schimanski Bernd, Schneider André (2019), The highly diverged trypanosomal MICOS complex is organized in a non‐essential integral membrane and an essential peripheral module, in Molecular Microbiology, mmi.14389-mmi.14389.
Mitoribosomal small subunit biogenesis in trypanosomes involves an extensive assembly machinery
Saurer Martin, Ramrath David J. F., Niemann Moritz, Calderaro Salvatore, Prange Céline, Mattei Simone, Scaiola Alain, Leitner Alexander, Bieri Philipp, Horn Elke K., Leibundgut Marc, Boehringer Daniel, Schneider André, Ban Nenad (2019), Mitoribosomal small subunit biogenesis in trypanosomes involves an extensive assembly machinery, in Science, 365(6458), 1144-1149.
Eine Translokase für Makromoleküle in Mitochondrien von Trypanosomen
Schneider André (2019), Eine Translokase für Makromoleküle in Mitochondrien von Trypanosomen, in BIOspektrum, 25(5), 504-506.
tRNA Biology in Trypanosomes
Shikha Shikha, Brogli Rebecca, Schneider André, Polacek Norbert (2019), tRNA Biology in Trypanosomes, in CHIMIA International Journal for Chemistry, 73(5), 395-405.
Mitochondrial protein import in trypanosomatids: Variations on a theme or fundamentally different?
Schneider André (2018), Mitochondrial protein import in trypanosomatids: Variations on a theme or fundamentally different?, in PLOS Pathogens, 14(11), e1007351-e1007351.
The Diverged Trypanosome MICOS Complex as a Hub for Mitochondrial Cristae Shaping and Protein Import
Kaurov Iosif, Vancová Marie, Schimanski Bernd, Cadena Lawrence Rudy, Heller Jiří, Bílý Tomáš, Potěšil David, Eichenberger Claudia, Bruce Hannah, Oeljeklaus Silke, Warscheid Bettina, Zdráhal Zbyněk, Schneider André, Lukeš Julius, Hashimi Hassan (2018), The Diverged Trypanosome MICOS Complex as a Hub for Mitochondrial Cristae Shaping and Protein Import, in Current Biology, 28(21), 3393-3407.e5.
Failure is not an option – mitochondrial genome segregation in trypanosomes
Schneider André, Ochsenreiter Torsten (2018), Failure is not an option – mitochondrial genome segregation in trypanosomes, in Journal of Cell Science, 131(18), jcs221820-jcs221820.
Evolutionary shift toward protein-based architecture in trypanosomal mitochondrial ribosomes
Ramrath David J. F., Niemann Moritz, Leibundgut Marc, Bieri Philipp, Prange Céline, Horn Elke K., Leitner Alexander, Boehringer Daniel, Schneider André, Ban Nenad (2018), Evolutionary shift toward protein-based architecture in trypanosomal mitochondrial ribosomes, in Science, eaau7735-eaau7735.
Independent evolution of functionally exchangeable mitochondrial outer membrane import complexes
Vitali Daniela G, Käser Sandro, Kolb Antonia, Dimmer Kai S, Schneider Andre, Rapaport Doron (2018), Independent evolution of functionally exchangeable mitochondrial outer membrane import complexes, in eLife, 7, 1-22.
The pseudo-dimeric tyrosyl-tRNA synthetase of T. brucei aminoacylates cytosolic and mitochondrial tRNA Tyr and requires both monomeric units for activity
Käser Sandro, Glauser Isabelle, Rettig Jochen, Schneider André (2018), The pseudo-dimeric tyrosyl-tRNA synthetase of T. brucei aminoacylates cytosolic and mitochondrial tRNA Tyr and requires both monomeric units for activity, in Molecular and Biochemical Parasitology, 221, 52-55.
Dihydrofolate reductase and membrane translocation: evolution of a classic experiment: Classic landmark papers, irrespective of their age, can teach students how best science is practiced and inspire new experiments.
Schneider André (2018), Dihydrofolate reductase and membrane translocation: evolution of a classic experiment: Classic landmark papers, irrespective of their age, can teach students how best science is practiced and inspire new experiments., in EMBO reports, e45692.
Molecular model of the mitochondrial genome segregation machinery in Trypanosoma brucei
Hoffmann Anneliese, Käser Sandro, Jakob Martin, Amodeo Simona, Peitsch Camille, Týč Jiří, Vaughan Sue, Zuber Benoît, Schneider André, Ochsenreiter Torsten (2018), Molecular model of the mitochondrial genome segregation machinery in Trypanosoma brucei, in Proceedings of the National Academy of Sciences, 201716582-201716582.

Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Turbolader für die Zellmaschinerie Medienmitteilung der Universität Bern German-speaking Switzerland 2019
Media relations: print media, online media Wie eine Proteinfabrik zusammengebaut wird Medienmitteilung der Universität Bern / ETH Zürich, Hochschulkommunikation German-speaking Switzerland 2019
Media relations: print media, online media Eine ganz besondere Proteinmaschinerie Medienmitteilung der Universität Bern / ETH Zürich, Hochschulkommunikation German-speaking Switzerland 2018
Media relations: print media, online media Neuer Schwachpunkt beim Erreger der Schlafkrankheit entdeckt Medienmitteilung der Universität Bern German-speaking Switzerland 2018

Associated projects

Number Title Start Funding scheme
156940 Mitochondrial biogenesis in the unicellular parasite Trypanosoma brucei 01.01.2015 Project funding (Div. I-III)

Abstract

Mitochondrial biogenesis has been investigated in great detail in yeast and mammals, that from a global view are closely related. My research group is studying mitochondrial biogenesis in the parasitic protozoan Trypanosoma brucei, which is phylogenetically essentially unrelated to yeast an mammals. During the last grant period we have discovered and characterized the subunit composition of the translocases in the outer (ATOM complex and pATOM36) and the inner mitochondrial membranes (TIM complex), which mediate mitochondrial protein import. Moreover, we have identified four novel outer membrane components of the trypanosomatid-specific tripartite attachment complex (TAC), which is essential for mitochondrial DNA inheritance. Finally, we have discovered a complex consisting of eight proteins, that likely facilitates cristae formation and thus might be the trypanosomal MICOS complex. - The functions of these trypanosomal protein assemblies are conserved and essential for mitochondrial biogenesis in all eukaryotes. However, their composition is dramatically different from their counterparts in yeast and mammals. The objectives of this research proposal are: To study mitochondrial protein import in trypanosomes•We will investigate the substrate specificity of the ATOM complex import receptors ATOM46 and ATOM69 and determine the molecular basis for it.•We will analyze the membrane topology of the outer membrane biogenesis factor pATOM36 and investigate how it mediates assembly and/or membrane insertion of outer membrane proteins.•We will identify and analyze the protein translocation pore(s) and the import motor of the TIM complex. To study mitochondrial DNA inheritance in trypanosomes•We will analyze the two step biogenesis pathway of the four newly discovered outer membrane TAC subunits. We will determine which cis-elements in these proteins and which trans-acting factors are responsible for OM targeting and lateral sorting to the TAC. •We will identify the elusive integral inner membrane subunit(s) of the TAC and study its (their) biogenesis. To characterize the non canonical trypanosomal MICOS complex•We will analyze the functions of the eight trypanosomal MICOS subunits and determine, whether they form specialized subcomplexes that are implicated in the formation of cristae junctions and outer membrane contact sites, respectively. We will also investigate which MICOS subunits form oligomers. To investigate quality control pathways triggered by mitochondrial dysfunction•Inhibition of mitochondrial protein import results in the rapid degradation of mislocalized proteins by the cytosolic proteasome. We will identify the cis-elements on the mislocalized proteins and the trans-acting factors that execute and control their cytosolic degradation.The expected results from this proposal will allow for a comparative analysis of mitochondrial biogenesis, between yeast/mammals and the essentially unrelated trypanosomes. This comparison will be based on functional features of the biogenesis factors rather than on in silico analyses. Thus, it will be possible to decide which aspects of mitochondrial biogenesis are conserved and which ones are different in the two types of systems. The few conserved components will provide insight into the early evolutionary history of mitochondria. The non-conserved factors may illustrate alternative solutions to the same biological problems. Moreover, functionally analogous components that are structurally not conserved will allow to define basic features of biogenesis factors, that are shared, not due to common descent, but because of functional constraints.
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