Dynamics of the Mitochondrial Proteome and Integration into Signalling Networks
Prof. Dr. Bettina Warscheid (Biochemistry and Functional Proteomics, Institute of Biologie II and BIOSS Centre for Biological Signalling Studies, University of Freiburg)
Mitochondria are highly dynamic entities and comprise the second largest proteome in the cell. Thus, tight regulation of mitochondrial proteome homeostasis is crucial for the maintenance of mitochondrial and cellular fitness. Dysregulation of mitochondrial function has been implicated in the pathogenesis of a variety of severe human disorders including cancer, neurodegeneration and ageing. Alterations in steady-state levels of mitochondrial proteins are often used as discriminants between conditions, but knowledge about the regulation and the dynamics of the mitochondrial proteome under perturbation is largely incomplete.
We recently discovered that the import rate of nuclear-encoded precursor proteins into mitochondria modulates the activity of the proteasome (Wrobel et al., 2015). We proposed that this response pathway, termed unfolded protein response activated by mistargeting of proteins (UPRam), is beneficial for the cell. Responses to defective mitochondrial protein import also involved modulation of the structure and function of genetic information and reshaping of metabolic networks in the cell, but the underlying molecular mechanisms have remained unknown. In this project, we want to better understand mitochondrial proteome dynamics and the integration of mitochondria into larger cellular protein networks to promote and maintain the fitness of a cell.
Selected publications (last 5 years):
- Charting organellar importomes by quantitative mass spectrometry.
Peikert CD, Mani J, Morgenstern M, Sandro K, Knapp B, Wenger C, Harsman A, Oeljeklaus S, Schneider A*, Warscheid B*.
Nat Commun. 2017; DOI: 10.1038/NCOMMS15272.
- The non-canonical mitochondrial inner membrane presequence translocase of trypanosomatids contains two essential rhomboid-like proteins.
Harsman A, Oeljeklaus S, Wenger C, Huot JL, Warscheid B*, Schneider A*.
Nat Commun. 2016; 7:13707.
- Mitochondrial protein synthesis adapts to influx of nuclear-encoded protein.
Richter-Dennerlein R, Oeljeklaus S, Lorenzi I, Ronsör C, Bareth B, Schendzielorz AB, Wang C, Warscheid B, Rehling P, Dennerlein S.
Cell. 2016; 167(2):471-83.
- Outer membrane protein functions as integrator of protein import and DNA inheritance in mitochondria.
Käser S, Oeljeklaus S, Týč J, Vaughan S, Warscheid B*, Schneider A*.
Proc Natl Acad Sci U S A. 2016; 113(31):E4467-75.
- Mitochondrial OXA translocase plays a major role in biogenesis of inner-membrane proteins.
Stiller SB, Höpker J, Oeljeklaus S, Schütze C, Schrempp SG, Vent-Schmidt J, Horvath SE, Frazier AE, Gebert N, van der Laan M, Bohnert M, Warscheid B, Pfanner N, Wiedemann N.
Cell Metab. 2016; 23(5):901-8.
- MITRAC7 acts as a COX1-specific chaperone and reveals a checkpoint during cytochrome c oxidase assembly.
Dennerlein S, Oeljeklaus S, Jans D, Hellwig C, Bareth B, Jakobs S, Deckers M, Warscheid B, Rehling P.
Cell Reports. 2015; 12:1644-1655.
- Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol.
Wrobel L, Topf U, Bragoszewski P, Wiese S, Sztolsztener ME, Oeljeklaus S, Varabyova A, Lirski M, Chroscicki P, Mroczek S, Januszewicz E, Dziembowski A, Koblowska M, Warscheid B*, Chacinska A*.
Nature. 2015; 524:485-8.
- Mitochondrial protein import receptors in Kinetoplastids reveal convergent evolution over large phylogenetic distances.
Mani J, Desy S, Niemann M, Chanfon A, Oeljeklaus S, Pusnik A, Schmidt O, Gerbeth C, Meisinger C, Warscheid B, Schneider A.
Nat Commun. 2015; 6:6646.
- SILAC labeling of yeast for the study of membrane protein complexes.
Oeljeklaus S, Schummer A, Suppanz I, Warscheid B.
Methods Mol Biol. 2014; 1188:23-46.
- Coupling of mitochondrial import and export translocases by receptor-mediated supercomplex formation.
Qiu J, Wenz LS, Zerbes RM, Oeljeklaus S, Bohnert M, Stroud DA, Wirth C, Ellenrieder L, Thornton N, Kutik S, Wiese S, Schulze-Specking A, Zufall N, Chacinska A, Guiard B, Hunte C, Warscheid B, van der Laan M, Pfanner N, Wiedemann N, Becker T.
Cell. 2013; 154(3):596-608.
- Mitochondrial outer membrane proteome of Trypanosoma brucei reveals novel factors required to maintain mitochondrial morphology.
Niemann M, Wiese S, Mani J, Chanfon A, Jackson C, Meisinger C, Warscheid B*, Schneider A.*
Mol Cell Proteomics. 2013; 12(2):515-28.
- MITRAC links mitochondrial protein translocation to respiratory-chain assembly and translational regulation.
Mick DU, Dennerlein S, Wiese H, Reinhold R, Pacheau-Grau D, Lorenzi I, Sasarman F, Weraarpachai W, Shoubridge EA, Warscheid B, Rehling P.
Cell. 2012; 151(7):1528-41.