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The mitochondrial methylation potential gates mitoribosome assembly

Author

Listed:
  • Ruth I. C. Glasgow

    (Karolinska Institutet)

  • Vivek Singh

    (Karolinska Institutet
    Stockholm University)

  • Lucía Peña-Pérez

    (Karolinska University Hospital
    Karolinska Institutet)

  • Alissa Wilhalm

    (Karolinska Institutet)

  • Marco F. Moedas

    (Karolinska Institutet
    Karolinska University Hospital)

  • David Moore

    (Karolinska Institutet)

  • Florian A. Rosenberger

    (Karolinska Institutet
    Karolinska Institutet)

  • Xinping Li

    (Max-Planck Institute for Biology of Ageing)

  • Ilian Atanassov

    (Max-Planck Institute for Biology of Ageing)

  • Mira Saba

    (Karolinska Institutet)

  • Miriam Cipullo

    (Karolinska Institutet)

  • Joanna Rorbach

    (Karolinska Institutet)

  • Anna Wedell

    (Karolinska University Hospital
    Karolinska Institutet)

  • Christoph Freyer

    (Karolinska Institutet
    Karolinska University Hospital)

  • Alexey Amunts

    (University of Münster
    Max Planck Institute of Molecular Physiology)

  • Anna Wredenberg

    (Karolinska Institutet
    Karolinska University Hospital)

Abstract

S-adenosylmethionine (SAM) is the principal methyl donor in cells and is essential for mitochondrial gene expression, influencing RNA modifications, translation, and ribosome biogenesis. Using direct long-read RNA sequencing in mouse tissues and embryonic fibroblasts, we show that processing of the mitochondrial ribosomal gene cluster fails in the absence of mitochondrial SAM, leading to an accumulation of unprocessed precursors. Proteomic analysis of ribosome fractions revealed these precursors associated with processing and assembly factors, indicating stalled biogenesis. Structural analysis by cryo-electron microscopy demonstrated that SAM-dependent methylation is required for peptidyl transferase centre formation during mitoribosome assembly. Our findings identify a critical role for SAM in coordinating mitoribosomal RNA processing and large subunit maturation, linking cellular methylation potential to mitochondrial translation capacity.

Suggested Citation

  • Ruth I. C. Glasgow & Vivek Singh & Lucía Peña-Pérez & Alissa Wilhalm & Marco F. Moedas & David Moore & Florian A. Rosenberger & Xinping Li & Ilian Atanassov & Mira Saba & Miriam Cipullo & Joanna Rorba, 2025. "The mitochondrial methylation potential gates mitoribosome assembly," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60977-x
    DOI: 10.1038/s41467-025-60977-x
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