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

  1. Désirée Schatton
  2. Giada Di Pietro
  3. Karolina Szczepanowska
  4. Matteo Veronese
  5. Marie-Charlotte Marx
  6. Kristina Braunöhler
  7. Esther Barth
  8. Stefan Müller
  9. Patrick Giavalisco
  10. Thomas Langer
  11. Aleksandra Trifunovic
  12. Elena I Rugarli

  • Curated by eLife

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    Evaluation Summary:

    This paper is of interest for cell biologists studying metabolism and its regulation during the cell cycle, as it demonstrates cross-talk between the CLUH protein, involved in mitochondrial function regulation and metabolism, and astrin, a protein functionally involved in cell division through regulation of centrosome integrity. This physical and functional interaction serves as a hub to integrate the metabolism with cell cycle progression.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

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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 (clustered mitochondria homolog) 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.

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  1. Version published to 10.7554/elife.74552 on eLife
  2. eLife

    Evaluation Summary:

    This paper is of interest for cell biologists studying metabolism and its regulation during the cell cycle, as it demonstrates cross-talk between the CLUH protein, involved in mitochondrial function regulation and metabolism, and astrin, a protein functionally involved in cell division through regulation of centrosome integrity. This physical and functional interaction serves as a hub to integrate the metabolism with cell cycle progression.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

  3. eLife

    Reviewer #1 (Public Review):

    Cluh is a protein involved in regulation of mitochondrial protein expression at the post-transcriptional level. The manuscript begins by the identification of a new Cluh partner, astrin. Astrin is a protein described earlier as involved in centrosome stability and mTOR signaling. Using a variety of techniques the authors demonstrate an extremely interesting and important link between metabolism, also governed by mTOR, mitochondrial function and cell cycle progression. Cluh binds to mRNA encoding astrin and its longer isoform, astrin-1, thereby protecting the encoded protein from degradation. This interaction takes place in the interphase, and in the absence of astrin the Cluh protein changes its subcellular location. The interaction of Cluh with astrin does not affect the regulation of mitochondria-related gene expression. Both proteins are functionally linked to the major driver of metabolism and cell fate, mTOR.

    The manuscript is technically sound and convincing. Regulation described in this study sheds the light on how the cell integrates and fine-tunes various activities, which need to be coordinated with the cell fate decisions. However, further work is required to understand this process mechanistically and physiologically. The authors themselves discuss many open questions and research directions for the future. One of the most exciting questions is the spatial localization aspects of this regulation. Certainly, the results obtained here will initiate several additional studies. In summary, the paper provides very interesting insight into the relationship between important signaling proteins.

  4. eLife

    Reviewer #2 (Public Review):

    In this manuscript the authors identified a novel interaction between the RNA binding protein CLUH and the known mTOR regulator astrin, proposing an additional regulatory mechanism by which CLUH impacts mTOR signalling and therefore cellular metabolism. They study how loss of one affects the levels or localization of the other interactor and the downstream consequences for cellular metabolites and mTOR signaling.

    Strengths:
    The authors use detailed molecular biological and biochemical techniques to reveal that CLUH only interacts with the full length form of astrin (astrin-1), with the shorter isoform (astrin-2) being a product of several downstream translation start sites. This suggests an interesting coupling of the translational regulation of astrin with its ability to regulate CLUH localization. They show that loss of astrin leads to a striking redistribution of CLUH to focal adhesions, whereas overexpression of astrin-1 but not astrin-2 sequesters some of CLUH to the centrosome. Loss of astrin does not mimic the effect that loss of CLUH has on mitochondrial morphology and respiratory function, supporting the notion that CLUH remains functional in this aspect despite its relocalization. Using proteomics and metabolomics of starved cells, the authors show that both proteins are involved in metabolic rewiring of the cell.

    Weaknesses:
    It remains unclear whether the mislocalization of CLUH upon loss of astrin has any consequences on metabolic rewiring, as astrin is a known interactor of the mTORC1 component Raptor and therefore loss of astrin may affect cellular metabolism only through this axis and not via CLUH mislocalization. This is supported by the finding that the metabolic profiles of CLUH and SPAG5 (=astrin) KO cells are almost polar opposites. The study is still lacking a mechanistic rescue experiment to test the claim that astrin is a negative regulator of CLUH.

    Summary
    The authors have presented convincing evidence for the interaction between two mTOR regulators, CLUH and astrin. Astrin is important for the localization of CLUH and CLUH regulates the expression of astrin. However, this study still lacks the complete dissection of the individual vs. the combined effects of these proteins on cellular metabolism. To understand their impact, both individually and combined, will be very interesting to the field as the connections between regulation of the cell cycle and mitochondrial metabolism/biogenesis are still not well understood.

  5. Version published to 10.1101/2021.10.20.465082v2 on bioRxiv
  6. Version published to 10.1101/2021.10.20.465082v1 on bioRxiv