The mitochondrial methylation potential gates mitoribosome assembly
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 processin...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-06-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60977-x |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849707167961055232 |
|---|---|
| author | 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 Anna Wredenberg |
| author_facet | 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 Anna Wredenberg |
| author_sort | Ruth I. C. Glasgow |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-261cdea9e8a14f608ae2e568edda9cd7 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-261cdea9e8a14f608ae2e568edda9cd72025-08-20T03:16:00ZengNature PortfolioNature Communications2041-17232025-06-0116111810.1038/s41467-025-60977-xThe mitochondrial methylation potential gates mitoribosome assemblyRuth I. C. Glasgow0Vivek Singh1Lucía Peña-Pérez2Alissa Wilhalm3Marco F. Moedas4David Moore5Florian A. Rosenberger6Xinping Li7Ilian Atanassov8Mira Saba9Miriam Cipullo10Joanna Rorbach11Anna Wedell12Christoph Freyer13Alexey Amunts14Anna Wredenberg15Department of Medical Biochemistry and Biophysics, Karolinska InstitutetDepartment of Medical Biochemistry and Biophysics, Karolinska InstitutetCentre for Inherited Metabolic Diseases, Karolinska University HospitalDepartment of Medical Biochemistry and Biophysics, Karolinska InstitutetDepartment of Medical Biochemistry and Biophysics, Karolinska InstitutetDepartment of Medical Biochemistry and Biophysics, Karolinska InstitutetDepartment of Medical Biochemistry and Biophysics, Karolinska InstitutetMax-Planck Institute for Biology of AgeingMax-Planck Institute for Biology of AgeingDepartment of Medical Biochemistry and Biophysics, Karolinska InstitutetDepartment of Medical Biochemistry and Biophysics, Karolinska InstitutetDepartment of Medical Biochemistry and Biophysics, Karolinska InstitutetCentre for Inherited Metabolic Diseases, Karolinska University HospitalDepartment of Medical Biochemistry and Biophysics, Karolinska InstitutetUniversity of MünsterDepartment of Medical Biochemistry and Biophysics, Karolinska InstitutetAbstract 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.https://doi.org/10.1038/s41467-025-60977-x |
| spellingShingle | 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 Anna Wredenberg The mitochondrial methylation potential gates mitoribosome assembly Nature Communications |
| title | The mitochondrial methylation potential gates mitoribosome assembly |
| title_full | The mitochondrial methylation potential gates mitoribosome assembly |
| title_fullStr | The mitochondrial methylation potential gates mitoribosome assembly |
| title_full_unstemmed | The mitochondrial methylation potential gates mitoribosome assembly |
| title_short | The mitochondrial methylation potential gates mitoribosome assembly |
| title_sort | mitochondrial methylation potential gates mitoribosome assembly |
| url | https://doi.org/10.1038/s41467-025-60977-x |
| work_keys_str_mv | AT ruthicglasgow themitochondrialmethylationpotentialgatesmitoribosomeassembly AT viveksingh themitochondrialmethylationpotentialgatesmitoribosomeassembly AT luciapenaperez themitochondrialmethylationpotentialgatesmitoribosomeassembly AT alissawilhalm themitochondrialmethylationpotentialgatesmitoribosomeassembly AT marcofmoedas themitochondrialmethylationpotentialgatesmitoribosomeassembly AT davidmoore themitochondrialmethylationpotentialgatesmitoribosomeassembly AT florianarosenberger themitochondrialmethylationpotentialgatesmitoribosomeassembly AT xinpingli themitochondrialmethylationpotentialgatesmitoribosomeassembly AT ilianatanassov themitochondrialmethylationpotentialgatesmitoribosomeassembly AT mirasaba themitochondrialmethylationpotentialgatesmitoribosomeassembly AT miriamcipullo themitochondrialmethylationpotentialgatesmitoribosomeassembly AT joannarorbach themitochondrialmethylationpotentialgatesmitoribosomeassembly AT annawedell themitochondrialmethylationpotentialgatesmitoribosomeassembly AT christophfreyer themitochondrialmethylationpotentialgatesmitoribosomeassembly AT alexeyamunts themitochondrialmethylationpotentialgatesmitoribosomeassembly AT annawredenberg themitochondrialmethylationpotentialgatesmitoribosomeassembly AT ruthicglasgow mitochondrialmethylationpotentialgatesmitoribosomeassembly AT viveksingh mitochondrialmethylationpotentialgatesmitoribosomeassembly AT luciapenaperez mitochondrialmethylationpotentialgatesmitoribosomeassembly AT alissawilhalm mitochondrialmethylationpotentialgatesmitoribosomeassembly AT marcofmoedas mitochondrialmethylationpotentialgatesmitoribosomeassembly AT davidmoore mitochondrialmethylationpotentialgatesmitoribosomeassembly AT florianarosenberger mitochondrialmethylationpotentialgatesmitoribosomeassembly AT xinpingli mitochondrialmethylationpotentialgatesmitoribosomeassembly AT ilianatanassov mitochondrialmethylationpotentialgatesmitoribosomeassembly AT mirasaba mitochondrialmethylationpotentialgatesmitoribosomeassembly AT miriamcipullo mitochondrialmethylationpotentialgatesmitoribosomeassembly AT joannarorbach mitochondrialmethylationpotentialgatesmitoribosomeassembly AT annawedell mitochondrialmethylationpotentialgatesmitoribosomeassembly AT christophfreyer mitochondrialmethylationpotentialgatesmitoribosomeassembly AT alexeyamunts mitochondrialmethylationpotentialgatesmitoribosomeassembly AT annawredenberg mitochondrialmethylationpotentialgatesmitoribosomeassembly |