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Mitochondrial lipid synthesis in Trypanosoma brucei: protein complexes forming lipids and lipids forming protein complexes

English title Mitochondrial lipid synthesis in Trypanosoma brucei: protein complexes forming lipids and lipids forming protein complexes
Applicant Bütikofer Peter
Number 169355
Funding scheme Project funding (Div. I-III)
Research institution Institut für Biochemie und Molekulare Medizin Universität Bern
Institution of higher education University of Berne - BE
Main discipline Biochemistry
Start/End 01.11.2016 - 30.11.2020
Approved amount 600'000.00
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All Disciplines (2)

Discipline
Biochemistry
Molecular Biology

Keywords (7)

Membrane contact sites; Phospholipids; Phosphatidylethanolamine; Respiratory chain complexes; Trypanosoma brucei; Mitochondrion; Cardiolipin

Lay Summary (German)

Lead
Trypanosoma brucei ist ein einzelliger Parasit, der beim Menschen die afrikanische Schlafkrankheit und bei Nutztieren die Nagana-Seuche auslöst. Erfolgt keine rechtzeitige Behandlung der Patienten mit Medikamenten, verläuft die Krankheit tödlich. Leider sind die verfügbaren Medikamente veraltet und haben zum Teil schwere Nebenwirkungen. Damit neue Therapieansätze und Medikamente entwickelt werden können, braucht es die universitäre Grundlagenforschung.
Lay summary

Unsere Forschungsprojekte befassen sich mit der Frage, wie Trypanosomen die Grundbausteine von Membranen, die sogenannten Membranlipide, herstellen. Membranen bilden die Hüllen aller Zellen und deren Organellen und sind deshalb für jeden Organismus von essentieller Bedeutung. Dabei konzentrieren wir uns auf diejenigen Reaktionswege, mit denen die Membranlipide in den Kraftwerken der Zelle, den Mitochondrien, hergestellt werden. Unsere Forschung hat gezeigt, dass gewisse biochemische Reaktionen bei der Herstellung dieser Membranlipide unentbehrlich sind für das Wachstum von Trypanosomen: Hemmt man diese Reaktionen, sterben die Parasiten ab. Die von uns untersuchten Membranlipide sind bei der Faltung und Funktion von Eiweissen, die bei der Energieproduktion in den Mitochondrien eine entscheidende Rolle spielen, beteiligt.

Mit der Identifizierung von Reaktionswegen und -mechanismen, die nur in Trypanosomen, nicht aber bei Mensch und Tier vorkommen, versuchen wir neue Ziele für die Entwicklung von Medikamenten gegen Schlafkrankheit und Nagana-Seuche zu finden. Zudem trägt unsere Forschung dazu bei, die Prozesse bei der Herstellung von mitochondriellen Membranlipiden in allen höheren Zellen besser zu verstehen.

Direct link to Lay Summary Last update: 23.09.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Mitochondrial sphingosine-1-phosphate lyase is essential for phosphatidylethanolamine synthesis and survival of Trypanosoma brucei
Dawoody Nejad Ladan, Stumpe Michael, Rauch Monika, Hemphill Andrew, Schneiter Roger, Bütikofer Peter, Serricchio Mauro (2020), Mitochondrial sphingosine-1-phosphate lyase is essential for phosphatidylethanolamine synthesis and survival of Trypanosoma brucei, in Scientific Reports, 10(1), 8268-8268.
Depletion of cardiolipin induces major changes in energy metabolism in Trypanosoma brucei bloodstream forms
Serricchio Mauro, Hierro‐Yap Carolina, Schädeli David, Ben Hamidane Hisham, Hemphill Andrew, Graumann Johannes, Zíková Alena, Bütikofer Peter (2020), Depletion of cardiolipin induces major changes in energy metabolism in Trypanosoma brucei bloodstream forms, in The FASEB Journal, fj.2020015-fj.2020015.
Cardiolipin depletion–induced changes in the Trypanosoma brucei proteome
Schädeli David, Serricchio Mauro, Ben Hamidane Hisham, Loffreda Alessio, Hemphill Andrew, Beneke Tom, Gluenz Eva, Graumann Johannes, Bütikofer Peter (2019), Cardiolipin depletion–induced changes in the Trypanosoma brucei proteome, in The FASEB Journal, 33(12), 13161-13175.
Anti-parasitic dinuclear thiolato-bridged arene ruthenium complexes alter the mitochondrial ultrastructure and membrane potential in Trypanosoma brucei bloodstream forms
Jelk Jennifer, Balmer Vreni, Stibal David, Giannini Federico, Süss-Fink Georg, Bütikofer Peter, Furrer Julien, Hemphill Andrew (2019), Anti-parasitic dinuclear thiolato-bridged arene ruthenium complexes alter the mitochondrial ultrastructure and membrane potential in Trypanosoma brucei bloodstream forms, in Experimental Parasitology, 205, 107753-107753.
Scrambling of natural and fluorescently tagged phosphatidylinositol by reconstituted G protein–coupled receptor and TMEM16 scramblases
Wang Lei, Iwasaki Yugo, Andra Kiran K., Pandey Kalpana, Menon Anant K., Bütikofer Peter (2018), Scrambling of natural and fluorescently tagged phosphatidylinositol by reconstituted G protein–coupled receptor and TMEM16 scramblases, in Journal of Biological Chemistry, 293(47), 18318-18327.
TbLpn, a key enzyme in lipid droplet formation and phospholipid metabolism, is essential for mitochondrial integrity and growth of Trypanosoma brucei Role of lipin in T. brucei growth
Dawoody Nejad Ladan, Serricchio Mauro, Jelk Jennifer, Hemphill Andrew, Bütikofer Peter (2018), TbLpn, a key enzyme in lipid droplet formation and phospholipid metabolism, is essential for mitochondrial integrity and growth of Trypanosoma brucei Role of lipin in T. brucei growth, in Molecular Microbiology, 109(1), 105-120.
Cross-species complementation of bacterial- and eukaryotic-type cardiolipin synthases
Gottier Petra, Serricchio Mauro, Vitale Rita, Corcelli Angela, Buetikofer Peter (2017), Cross-species complementation of bacterial- and eukaryotic-type cardiolipin synthases, in Microbial Cell, 4(11), 376-383.

Collaboration

Group / person Country
Types of collaboration
Prof. Michael Schlame, New York University, New York United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Johannes Graumann, Weill Cornell Medicine - Qatar Qatar (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Alena Zikova, Institute of Parasitology, Czech Academy of Sciences, Ceske Budejovice Czech Republic (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Andrew Hemphill, Institute of Parasitology, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Eva Gluenz, Sir William Dunn School of Pathology, University of Oxford Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. André Schneider, Departement für Chemie & Biochemie, Universität Bern, Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Anant K. Menon, Department of Biochemistry, Weill Cornell Medical College, New York United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
37th Annual Swiss Trypanosomatid Meeting Poster CLDP43, a novel cardiolipin synthase-dependent protein affecting cardiolipin synthesis and mitochondrial integrity in T. brucei 15.01.2020 Leysin, Switzerland Bütikofer Peter; Loffreda Alessio;
37th Annual Swiss Trypanosomatid Meeting Talk given at a conference The endoplasmic reticulum membrane protein complex (EMC): interactome and function in Trypanosoma brucei 15.01.2020 Leysin, Switzerland Bütikofer Peter; Iyer Advaitha;
36th Annual Swiss Trypanosomatid Meeting Poster Characterization of the ER membrane protein complex (EMC) in T. brucei 09.01.2019 Leysin, Switzerland Iyer Advaitha; Bütikofer Peter;
36th Annual Swiss Trypanosomatid Meeting Talk given at a conference A cardiolipin-dependent protein affecting mitochondrial function and phospholipid synthesis in Trypanosoma brucei 09.01.2019 Leysin, Switzerland Loffreda Alessio; Bütikofer Peter;
35th Annual Swiss Trypanosomatid Meeting Poster Unique features of PE synthesis and characterisation of a START-domain containing protein in T. brucei 10.01.2018 Leysin, Switzerland Loffreda Alessio; Bütikofer Peter;


Self-organised

Title Date Place
37th Annual Swiss Trypanosomatid Meeting 15.01.2020 Leysin, Switzerland
36th Annual Swiss Trypanosomatid Meeting 09.01.2019 Leysin, Switzerland
Cardiolipin as Key Lipid of Mitochondria in Health and Disease 01.10.2017 Bari, Italy

Associated projects

Number Title Start Funding scheme
149353 Mitochondrial lipid synthesis in the model eukaryote, Trypanosoma brucei: identification of lipid biosynthesis complexes and contributions of individual pathways to mitochondrial structure and function 01.11.2013 Project funding (Div. I-III)

Abstract

Trypanosoma brucei is the causative agent of human African sleeping sickness and nagana, a related livestock disease, in sub-Saharan Africa. During their life cycle, T. brucei parasites live in the blood and extracellular fluids of the mammalian hosts and colonize several organs in the insect vector, the tsetse fly. Because T. brucei can be cultured axenically in vitro and is amenable to reverse genetics, including inducible RNAi-mediated silencing of gene expression and gene knock-out by homologous recombination, it is often used as model organism for molecular parasitology. However, T. brucei has also emerged as unicellular model eukaryote to study general biological processes, including mitochondrial function and membrane lipid metabolism. The main research focus of our laboratory is on the identification and characterization of the pathways of glycerophospholipid synthesis in T. brucei, to reveal their importance for parasite viability and to gain further insight into mechanisms involved in eukaryotic glycerophospholipid homeostasis. In addition, we are interested to study the roles of membrane lipids in protein function in the trypanosome mitochondrion.It has been shown in other eukaryotes that the stability and activity of mitochondrial respiratory chain complexes and the generation of the mitochondrial membrane potential is dependent on the presence of the mitochondrial signature lipid cardiolipin (CL) in the inner mitochondrial membrane. By using our T. brucei cell lines in which we can induce changes in the levels of CL and of its biosynthetic precursor phosphatidylglycerol (PG), we have recently been able to demonstrate similar events in trypanosomes. In the first part of the proposal, we plan to use these cells in combination with an unbiased approach to identify novel CL-dependent proteins and study their importance for mitochondrial function. The fact that the mitochondrion in T. brucei undergoes major morphological and functional changes during differentiation between different life cycle forms provides a unique opportunity to study such questions under two metabolically very different conditions, i.e. in the absence or presence of key mitochondrial components and functions. In addition, we will exploit our preliminary observations that two key enzymes in mitochondrial glycerophospholipid synthesis, TbPGPS and TbCLS, are likely present in the same high molecular mass protein complex and propose to identify their interaction partners. Finally, identification of the substrates of TbPGPS and TbCLS, which may lead to the discovery of a novel catalytic mechanism for PG formation, completes this main part of the grant application.In the second part, we will focus on de novo synthesis of phosphatidylethanolamine (PE) via the CDP-ethanolamine branch of the Kennedy pathway, a reaction sequence that we have previously shown to be essential for T. brucei viability. Since the initial reactions to produce the lipophilic substrate for PE synthesis occur in glycosomes whereas the terminal reaction takes place in the perinuclear endoplasmic reticulum, we plan to localize all intermediate enzymatic steps to obtain a complete map for PE synthesis in T. brucei. Such a comprehensive analysis of the route for PE formation has not been undertaken in any eukaryote before.The third part of the proposal is based on our very recent observations aimed at elucidating contact sites between the endoplasmic reticulum and the mitochondrion to understand membrane lipid trafficking between these two organelles. We have localized homologs of an endoplasmic reticulum-mitochondrion tethering complex in T. brucei and found that down-regulation of a single component of this complex causes a growth defect of trypanosomes. We will study a possible connection of this complex with a highly purified T. brucei membrane fraction that resembles mitochondria-associated membranes described previously in other eukaryotes. Preliminary proteomic and lipidomic analyses suggest the involvement of this fraction in lipid synthesis and transport in T. brucei parasites.
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