The mitochondrial methylation potential gates mitoribosome assembly

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 Rorbach, Anna Wedell, Christoph Freyer (), Alexey Amunts () and Anna Wredenberg ()
Additional contact information
Ruth I. C. Glasgow: Karolinska Institutet
Vivek Singh: Karolinska Institutet
Lucía Peña-Pérez: Karolinska University Hospital
Alissa Wilhalm: Karolinska Institutet
Marco F. Moedas: Karolinska Institutet
David Moore: Karolinska Institutet
Florian A. Rosenberger: 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
Christoph Freyer: Karolinska Institutet
Alexey Amunts: University of Münster
Anna Wredenberg: Karolinska Institutet

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60977-x

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