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

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 Poveda-Huertes, Alexandra Schwierzok, Henrike Pommerening, Stanka Matic, Jan Brix, Albert Sickmann, Claudine Kraft, Jörn Dengjel, Sven Dennerlein, Tilman Brummer, F.-Nora Vögtle () and Chris Meisinger ()
Additional contact information
Corvin Walter: 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
Pablo Sánchez-Martín: University of Freiburg
Zehan Hu: University of Fribourg
Abhishek Aich: University Medical Center 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
Jörn Dengjel: University of Fribourg
Sven Dennerlein: University Medical Center Göttingen
Tilman Brummer: University of Freiburg
F.-Nora Vögtle: University of Freiburg
Chris Meisinger: University of Freiburg

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24426-9

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DOI: 10.1038/s41467-021-24426-9

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