Control of mitochondrial metabolism by cytosolic signalling cascades

Mitochondria are central organelles in eukaryotic cells. Beside their important role in the production of cellular ATP by OXPHOS and many biosynthesis pathways, mitochondria represent the central switchpoint in the induction of programmed cell death. Mitochondrial dysfunction plays an important in role in the onset of many human diseases, particularly tumors and neurodegenerative diseases.

More than 99% of the mitochondrial proteins are nuclear encoded and have to be imported into the organelle after their synthesis as precursors in the cytosol. Several sophisticated transport machineries mediate recognition, transport, sorting and assembly of these precursors. We have identified signalling mechanism based on phophorylation by cytosolic and mitochondrial kinases that regulate biogenesis of mitochondrial proteins according to changes in the cellular requirements (see e.g. Schmidt et al., Cell 2011; Gerbeth et al., Cell Metab. 2013; Harbauer et al., Science 2014; Poveda-Huertes et al., Mol. Cell 2020; Walter et al. Nat. Commun. 2021).

Our main research interest is to understand how signalling mechanisms at the mitochondrial import machinery allow a dynamic adaptation of the mitochondrial proteome to changing cellular demands, e.g. by metabolic switches, cell cycle phases or stresses. Moreover, we aim to understand how dysfunctional organellar signalling pathways might contribute to the onset of e.g. neurodegeneration or cancer. We are studying these questions in different systems: from unicellular model organisms like S. cerevisiae and mouse models to human tissue culture and patient samples.

Keywords

Organellar signalling, Signaltansduction, mitochondrial biogenesis, Protein translocation, Metabolism, Warburg Effect; Neurodegeneration

10 selected publications

• Global kinome profiling reveals DYRK1A as critical activator of the human mitochondrial import machinery.
  Walter C, Marada A, Suhm T, Ernsberger R, Muders V, Kücükköse C, Sánchez-Martín P, Hu Z, Aich A, Loroch S, Solari FA, Poveda-Huertes D, Schwierzok A, Pommerening H, Matic S, Brix J, Sickmann A, Kraft C, Dengjel J, Dennerlein S, Brummer T, Vögtle FN, Meisinger C (2021).
  Nat. Commun. 12, 4284.
• An early mtUPR: Redistribution of the nuclear transcription factor Rox1 into mitochondria protects against intramitochondrial proteotoxic aggregates.
  Poveda-Huertes D, Matic S, Marada A, Habernig L, Licheva M, Myketin L, Gilsbach R, Tosal-Castano S, Papinski D, Mulica P, Kretz O, Kücükköse C, Taskin AA, Hein L, Kraft C, Büttner S, Meisinger C, Vögtle FN (2020).
  Mol. Cell 77, 180-188.
• Landscape of submitochondrial protein distribution.
  Vögtle FN, Burkhart JM, Gonczarowska-Jorge H, Kücükköse C, Taskin AA, Kopczynski D, Ahrends R, Mossmann D, Sickmann A, Zahedi RP, Meisinger C (2017).
  Nat. Commun. 8, 290.
• Identification of new channels by systematic analysis of the mitochondrial outer membrane.
  Krüger V, Becker T, Becker L, Montilla-Martinez M, Ellenrieder L, Vögtle FN, Meyer HE, Ryan MT, Wiedemann N, Warscheid B, Pfanner N, Wagner R, Meisinger C (2017).
  J Cell Biol. 216, 3485-3495.
• The fusogenic lipid phosphatidic acid promotes the biogenesis of mitochondrial outer membrane protein Ugo1.
  Vögtle FN, Keller M, Taskin AA, Horvath SE, Guan XL, Prinz C, Opalińska M, Zorzin C, van der Laan M, Wenk MR, Schubert R, Wiedemann N, Holzer M, Meisinger C (2015).
  J Cell Biol. 210, 951-60.
• Cell cycle-dependent regulation of mitochondrial preprotein translocase.
  Harbauer AB, Opalińska M, Gerbeth C, Herman JS, Rao S, Schönfisch B, Guiard B, Schmidt O, Pfanner N, Meisinger C (2014).
  Science 346, 1109-13.
• Amyloid-beta peptide induces mitochondrial dysfunction by inhibition of preprotein maturation.
  Mossmann D, Vögtle FN, Taskin AA, Teixeira PF, Ring J, Burkhart JM, Burger N, Pinho CM, Tadic J, Loreth D, Graff C, Metzger F, Sickmann A, Kretz O, Wiedemann N, Zahedi RP, Madeo F, Glaser E, Meisinger C (2014).
  Cell Metab. 20, 662-669.
• Regulation of mitochondrial protein import by cytosolic kinases.
  Schmidt O, Harbauer AB, Rao S, Eyrich B, Zahedi RP, Stojanovski D, Schönfisch B, Guiard B, Sickmann A, Pfanner N, Meisinger C (2011).
  Cell 144, 227-39.
• Global analysis of the mitochondrial N-proteome identifies a processing peptidase critical for protein stability.
  Vögtle FN, Wortelkamp S, Zahedi RP, Becker D, Leidhol, C, Gevaert K, Kellermann J, Voos W, Sickmann A, Pfanner N, Meisinger C (2009).
  Cell 139, 428-439.
• Machinery for protein sorting and assembly in the mitochondrial outer membrane.
  Wiedemann N, Kozjak V, Chacinska A, Schönfisch B, Rospert S, Ryan MT, Pfanner N, Meisinger C (2003).
  Nature 424, 565-71.