CLUH controls astrin-1 expression to couple mitochondrial metabolism to cell cycle progression

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Abstract

Proliferating cells undergo metabolic changes in synchrony with cell cycle progression and cell division. Mitochondria provide fuel, metabolites, and ATP during different phases of the cell cycle, however it is not completely understood how mitochondrial function and the cell cycle are coordinated. CLUH is a post-transcriptional regulator of mRNAs encoding mitochondrial proteins involved in oxidative phosphorylation and several metabolic pathways. Here, we show a role of CLUH in regulating the expression of astrin, which is involved in metaphase to anaphase progression, centrosome integrity, and mTORC1 inhibition. We find that CLUH binds both the SPAG5 mRNA and its product astrin, and controls the synthesis and the stability of the full-length astrin-1 isoform. We show that CLUH interacts with astrin-1 specifically during interphase. Astrin-depleted cells show mTORC1 hyperactivation and enhanced anabolism. On the other hand, cells lacking CLUH show decreased astrin levels and increased mTORC1 signaling, but cannot sustain anaplerotic and anabolic pathways. In absence of CLUH, cells fail to grow during G1, and progress faster through the cell cycle, indicating dysregulated matching of growth, metabolism and cell cycling. Our data reveal a role of CLUH in coupling growth signaling pathways and mitochondrial metabolism with cell cycle progression.

Data availability

Source data files have been provided for Figures 1, 2, 3, 4, 5, 6 and 7.The mass spectrometry proteomic data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifiers: PXD029142, PXD029145, PXD029156.

The following data sets were generated

1. Rugarli EI
2. et al
(2022) CLUH controls astrin-1 expression to couple mitochondrial metabolism to cell cycle progression
PRIDE. PXD029142.

https://www.ebi.ac.uk/pride/archive/projects/PXD029142
1. Rugarli EI
2. et al
(2022) CLUH controls astrin-1 expression to couple mitochondrial metabolism to cell cycle progression
PRIDE, PXD029145.

https://www.ebi.ac.uk/pride/archive/projects/PXD029145
1. Rugarli EI
2. et al
(2022) CLUH controls astrin-1 expression to couple mitochondrial metabolism to cell cycle progression
PRIDE, PXD029156.

https://www.ebi.ac.uk/pride/archive/projects/PXD029156

Article and author information

Author details

Desiree Schatton

Institute for Genetics, University of Cologne, Cologne, Germany

Competing interests
The authors declare that no competing interests exist.
Giada Di Pietro

Institute for Genetics, University of Cologne, Cologne, Germany

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The authors declare that no competing interests exist.
Karolina Szczepanowska

Institute for Mitochondrial Diseases and Ageing, University of Cologne, Cologne, Germany

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The authors declare that no competing interests exist.
Matteo Veronese

Institute for Genetics, University of Cologne, Cologne, Germany

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The authors declare that no competing interests exist.
Marie-Charlotte Marx

Institute for Genetics, University of Cologne, Cologne, Germany

Competing interests
The authors declare that no competing interests exist.
Kristina Braunöhler

Institute for Genetics, University of Cologne, Cologne, Germany

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The authors declare that no competing interests exist.
Esther Barth

Institute for Genetics, University of Cologne, Cologne, Germany

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The authors declare that no competing interests exist.
Stefan Müller

Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany

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The authors declare that no competing interests exist.
Patrick Giavalisco

Center for Molecular Medicine, University of Cologne, Cologne, Germany

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-4636-1827
Thomas Langer

Langer Department, Max Planck Institute for Biology of Ageing, Cologne, Germany

Competing interests
The authors declare that no competing interests exist.
Aleksandra Trifunovic

Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5472-3517
Elena I Rugarli

Institute for Genetics, University of Cologne, Cologne, Germany

For correspondence
elena.rugarli@uni-koeln.de

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5782-1067

Funding

Deutsche Forschungsgemeinschaft (269925409)

Elena I Rugarli

Deutsche Forschungsgemeinschaft (411422114-GRK 2550)

Elena I Rugarli

Max Planck Institute for Biology of Ageing (open access funding)

Thomas Langer

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.