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Molecular Bioenergetics

 

Structure and Function of Mitochondrial Complexes

Proteins are the molecules that form the structural basis and execute the vast majority of functions in all cells. Elucidating their structure and function and understanding their interactions and dynamics therefore forms the indispensable basis for achieving profound knowledge about physiology of an organism and to develop causal treatment strategies of human disease. In our quest to gain insight into the molecular basis of mitochondrial disease we currently focus on two topics:

1. Atomic structure and mechanism of mitochondrial complex I

We have elucidated the structure of mitochondrial complex I by X‐ray crystallography and aim at understanding its molecular mechanism by detailed functional analysis of site-directed mutants in the yeast genetic model Yarrowia lipolytica with respect to redox-driven proton translocation, control of the active/deactive transition and ROS formation. We use the information obtained by these studies to reach a detailed understanding of the pathophysiological mechanisms of human mutations causing mitochondrial disorders. To this end, complementary studies are performed in human (patient) cell lines.

2. Mitochondrial complexomics

Many mitochondrial functions are linked to the stable or transient formation of multiprotein complexes. For a comprehensive analysis of the inventory of such complexes in a given biological sample, we have developed complexome profiling. This approach links state of the art shotgun proteomics to the superior separation power of blue-native electrophoresis for native protein complexes. Protein-migration profiles of complexes of up to a size of 30 MDa are obtained that are then analyzed by bottom-up hierarchical clustering for the unbiased detection of their constituents. Complexome profiling allows for the discovery of functionally important components of macromolecular assemblies and assembly inter-mediates. Time course dependent complexome profiling provides comprehensive insights into the functional dynamics of protein-protein interactions. Our current goals are to obtain detailed insight into the assembly dynamics of mitochondrial complexes in health and disease and to decipher the composition and functional dynamics of the protein complexes associated with mitochondrial permeability transition.

Group leader

Prof. Dr. Ulrich Brandt
Tel.: +31(0)24 36 67098 
Fax: +31(0)24 36 16428
Email: 
Researcher-ID: C-4406-2008

    Contact

    Radboud Center for Mitochondrial Medicine
    Department of Pediatrics
    Radboud university medical center
    Geert Grooteplein-Zuid 10, Route 772
    6525 GA Nijmegen
    The Netherlands

    Recent publications

    1. Evolution and structural organization of the mitochondrial contact site (MICOS) complex and the mitochondrial intermembrane space bridging (MIB) complex. Huynen MA, Mühlmeister M, Gotthardt K, Guerrero-Castillo S, Brandt U. Biochim Biophys Acta. 2015 Oct 15. pii: S0167-4889(15)00362-6.

    2. Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma are highly dependent on oxidative phosphorylation. Birkenmeier K, Dröse S, Wittig I, Winkelmann R, Käfer V, Döring C, Hartmann S, Wenz T, Reichert AS, Brandt U, Hansmann ML. Int J Cancer. 2015 Nov 23. [Epub ahead of print] PubMed PMID: 26595876.

    3. Accessory NUMM (NDUFS6) subunit harbors a Zn-binding site and is essential for biogenesis of mitochondrial complex I. Kmita K, Wirth C, Warnau J, Guerrero-Castillo S, Hunte C, Hummer G, Kaila VRI, Zwicker K, Brandt U, Zickermann V. PNAS. 2015, epub ahead of print, doi:10.1073/pnas.1424353112.

    4. Structural biology. Mechanistic insight from the crystal structure of mitochondrial complex I. Zickermann V, Wirth C, Nasiri H, Siegmund K, Schwalbe H, Hunte C, Brandt U. Science. 2015 Jan 2;347(6217):44-9.

    5. Generator-specific targets of mitochondrial reactive oxygen species. Bleier L, Wittig I, Heide H, Steger M, Brandt U, Dröse S. Free Radic Biol Med. 2015 Jan;78:1-10.

    6. NOVA: a software to analyze complexome profiling data. Giese H, Ackermann J, Heide H, Bleier L, Dröse S, Wittig I, Brandt U, Koch I. Bioinformatics. 2015 Feb 1;31(3):440-1.

    7. The LYR protein subunit NB4M/NDUFA6 of mitochondrial complex I anchors an acyl carrier protein and is essential for catalytic activity.
      Angerer H, Radermacher M, Małkowska M, Steger M, Zwicker K, Heide H, Wittig I, Brandt U, Zickermann V. Proc Natl Acad Sci U S A. 2014 Apr 8;111(14):5207-12.

    8. Complexome profiling identifies TMEM126B as a component of the mitochondrial complex I assembly complex. Heide H, Bleier L, Steger M, Ackermann J, Dröse S, Schwamb B, Zörnig M, Reichert AS, Koch I, Wittig I, Brandt U. Cell Metab. 2012 Oct 3;16(4):538-49.

    9. A two-state stabilization-change mechanism for proton-pumping complex I. Brandt U. Biochim Biophys Acta. 2011 Oct;1807(10):1364-9.

    10. Functional dissection of the proton pumping modules of mitochondrial complex I. Dröse S, Krack S, Sokolova L, Zwicker K, Barth HD, Morgner N, Heide H, Steger M, Nübel E, Zickermann V, Kerscher S, Brutschy B, Radermacher M, Brandt U. PLoS Biol. 2011 Aug;9(8):e1001128.

    11. Functional modules and structural basis of conformational coupling in mitochondrial complex I. Hunte C, Zickermann V, Brandt U. Science. 2010 Jul 23;329(5990):448-51.

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