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DYRK1A signalling synchronizes the mitochondrial import pathways for metabolic rewiring

Author

Listed:
  • Adinarayana Marada

    (University of Freiburg)

  • Corvin Walter

    (University of Freiburg
    University of Freiburg)

  • Tamara Suhm

    (University of Freiburg)

  • Sahana Shankar

    (University of Freiburg)

  • Arpita Nandy

    (University of Freiburg
    University of Freiburg
    University of Freiburg)

  • Tilman Brummer

    (University of Freiburg
    University of Freiburg
    German Cancer Research Center (DKFZ))

  • Ines Dhaouadi

    (University of Freiburg)

  • F.-Nora Vögtle

    (DKFZ-ZMBH Alliance
    Heidelberg University
    University of Freiburg)

  • Chris Meisinger

    (University of Freiburg
    University of Freiburg
    University of Freiburg)

Abstract

Mitochondria require an extensive proteome to maintain a variety of metabolic reactions, and changes in cellular demand depend on rapid adaptation of the mitochondrial protein composition. The TOM complex, the organellar entry gate for mitochondrial precursors in the outer membrane, is a target for cytosolic kinases to modulate protein influx. DYRK1A phosphorylation of the carrier import receptor TOM70 at Ser91 enables its efficient docking and thus transfer of precursor proteins to the TOM complex. Here, we probe TOM70 phosphorylation in molecular detail and find that TOM70 is not a CK2 target nor import receptor for MIC19 as previously suggested. Instead, we identify TOM20 as a MIC19 import receptor and show off-target inhibition of the DYRK1A-TOM70 axis with the clinically used CK2 inhibitor CX4945 which activates TOM20-dependent import pathways. Taken together, modulation of DYRK1A signalling adapts the central mitochondrial protein entry gate via synchronization of TOM70- and TOM20-dependent import pathways for metabolic rewiring. Thus, DYRK1A emerges as a cytosolic surveillance kinase to regulate and fine-tune mitochondrial protein biogenesis.

Suggested Citation

  • Adinarayana Marada & Corvin Walter & Tamara Suhm & Sahana Shankar & Arpita Nandy & Tilman Brummer & Ines Dhaouadi & F.-Nora Vögtle & Chris Meisinger, 2024. "DYRK1A signalling synchronizes the mitochondrial import pathways for metabolic rewiring," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49611-4
    DOI: 10.1038/s41467-024-49611-4
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    References listed on IDEAS

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    1. Nils Wiedemann & Vera Kozjak & Agnieszka Chacinska & Birgit Schönfisch & Sabine Rospert & Michael T. Ryan & Nikolaus Pfanner & Chris Meisinger, 2003. "Machinery for protein sorting and assembly in the mitochondrial outer membrane," Nature, Nature, vol. 424(6948), pages 565-571, July.
    2. Corvin Walter & Adinarayana Marada & Tamara Suhm & Ralf Ernsberger & Vera Muders & Cansu Kücükköse & Pablo Sánchez-Martín & Zehan Hu & Abhishek Aich & Stefan Loroch & Fiorella Andrea Solari & Daniel P, 2021. "Global kinome profiling reveals DYRK1A as critical activator of the human mitochondrial import machinery," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    3. Elena Schmidt & Ines Dhaouadi & Isabella Gaziano & Matteo Oliverio & Paul Klemm & Motoharu Awazawa & Gerfried Mitterer & Eduardo Fernandez-Rebollo & Marta Pradas-Juni & Wolfgang Wagner & Philipp Hamme, 2018. "LincRNA H19 protects from dietary obesity by constraining expression of monoallelic genes in brown fat," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
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