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Global kinome profiling reveals DYRK1A as critical activator of the human mitochondrial import machinery

Author

Listed:
  • Corvin Walter

    (University of Freiburg
    University of Freiburg)

  • Adinarayana Marada

    (University of Freiburg)

  • Tamara Suhm

    (University of Freiburg)

  • Ralf Ernsberger

    (University of Freiburg)

  • Vera Muders

    (University of Freiburg)

  • Cansu Kücükköse

    (University of Freiburg
    University of Freiburg)

  • Pablo Sánchez-Martín

    (University of Freiburg)

  • Zehan Hu

    (University of Fribourg)

  • Abhishek Aich

    (University Medical Center Göttingen
    University of Göttingen)

  • Stefan Loroch

    (Leibniz Institut für Analytische Wissenschaften - ISAS - e.V.)

  • Fiorella Andrea Solari

    (Leibniz Institut für Analytische Wissenschaften - ISAS - e.V.)

  • Daniel Poveda-Huertes

    (University of Freiburg)

  • Alexandra Schwierzok

    (University of Freiburg)

  • Henrike Pommerening

    (University of Freiburg)

  • Stanka Matic

    (University of Freiburg)

  • Jan Brix

    (University of Freiburg)

  • Albert Sickmann

    (Leibniz Institut für Analytische Wissenschaften - ISAS - e.V.)

  • Claudine Kraft

    (University of Freiburg
    University of Freiburg)

  • Jörn Dengjel

    (University of Fribourg)

  • Sven Dennerlein

    (University Medical Center Göttingen)

  • Tilman Brummer

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

  • F.-Nora Vögtle

    (University of Freiburg
    University of Freiburg
    Center for Molecular Biology of Heidelberg University (ZMBH))

  • Chris Meisinger

    (University of Freiburg
    University of Freiburg
    University of Freiburg)

Abstract

The translocase of the outer mitochondrial membrane TOM constitutes the organellar entry gate for nearly all precursor proteins synthesized on cytosolic ribosomes. Thus, TOM presents the ideal target to adjust the mitochondrial proteome upon changing cellular demands. Here, we identify that the import receptor TOM70 is targeted by the kinase DYRK1A and that this modification plays a critical role in the activation of the carrier import pathway. Phosphorylation of TOM70Ser91 by DYRK1A stimulates interaction of TOM70 with the core TOM translocase. This enables transfer of receptor-bound precursors to the translocation pore and initiates their import. Consequently, loss of TOM70Ser91 phosphorylation results in a strong decrease in import capacity of metabolite carriers. Inhibition of DYRK1A impairs mitochondrial structure and function and elicits a protective transcriptional response to maintain a functional import machinery. The DYRK1A-TOM70 axis will enable insights into disease mechanisms caused by dysfunctional DYRK1A, including autism spectrum disorder, microcephaly and Down syndrome.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24426-9
    DOI: 10.1038/s41467-021-24426-9
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    References listed on IDEAS

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    1. R. John Ellis, 2003. "Plugging the transport gap," Nature, Nature, vol. 421(6925), pages 801-802, February.
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    Cited by:

    1. Natalie M. Niemi & Lia R. Serrano & Laura K. Muehlbauer & Catherine E. Balnis & Lianjie Wei & Andrew J. Smith & Keri-Lyn Kozul & Merima Forny & Olivia M. Connor & Edrees H. Rashan & Evgenia Shishkova , 2023. "PPTC7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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