Cell type–specific purifying selection of synonymous mitochondrial DNA variation

While somatic variants are well-characterized drivers of tumor evolution, their influence on cellular fitness in nonmalignant contexts remains understudied. We identified a mosaic synonymous variant (m.7076A > G) in the mitochondrial DNA (mtDNA)-encoded cytochrome c-oxidase subunit 1 (MT-CO1, p.Gly391=), present at homoplasmy in 47% of immune cells from a healthy donor. Single-cell multiomics revealed strong, lineage-specific selection against the m.7076G allele in CD8<sup>+</sup> effector memory T cells, but not other T cell subsets, mirroring patterns of purifying selection of pathogenic mtDNA alleles. The limited anticodon diversity of mitochondrial tRNAs forces m.7076G translation to rely on wobble pairing, unlike the Watson-Crick-Franklin pairing used for m.7076A. Mitochondrial ribosome profiling confirmed stalled translation of the m.7076G allele. Functional analyses demonstrated that the elevated translational and metabolic demands of short-lived effector T cells (SLECs) amplify dependence on MT-CO1, driving this selective pressure. These findings suggest that synonymous variants can alter codon syntax, impacting mitochondrial physiology in a cell type-specific manner.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-07-24
DOI
https://doi.org/10.1073/pnas.2505704122
Citations
3
Primary Topic
Single-cell and spatial transcriptomics
Type
article
Field-Weighted Citation Impact
2.42

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article

Cell type–specific purifying selection of synonymous mitochondrial DNA variation

Sebastian Zielinski, Tsion Abay, Robert R. Stickels, Mathias Munschauer et al.
3 citations
Proceedings of the National Academy of Sciences
Single-cell and spatial transcriptomics
2.42
article

Cell type–specific purifying selection of synonymous mitochondrial DNA variation

Sebastian Zielinski, Tsion Abay, Robert R. Stickels, Mathias Munschauer, Paul‐Lennard Mendez, Yajie Yin, Veronika Dimitrova, Lena Nitsch, Redmond P. Smyth, Patrick Yan, Ryan S. Dhindsa, Anne-Sophie Gribling-Burrer, Frank A. Buquicchio, Patrick Maschmeyer, Caleb A. Lareau, Ansuman T. Satpathy, Jacob C. Ulirsch, Yu-Hsin Hsieh, Jacob C. Gutierrez, William J. Greenleaf, Katalin Sándor, Bence Dániel, Petra Knaus, Leif S. Ludwig, Anshul Kundaje, Benan Nalbant, Zhuang Miao, Manpreet Meyer, Vincent Liu, Fangyi Wang
article en
3 citations

Abstract

While somatic variants are well-characterized drivers of tumor evolution, their influence on cellular fitness in nonmalignant contexts remains understudied. We identified a mosaic synonymous variant (m.7076A > G) in the mitochondrial DNA (mtDNA)-encoded cytochrome c-oxidase subunit 1 (MT-CO1, p.Gly391=), present at homoplasmy in 47% of immune cells from a healthy donor. Single-cell multiomics revealed strong, lineage-specific selection against the m.7076G allele in CD8<sup>+</sup> effector memory T cells, but not other T cell subsets, mirroring patterns of purifying selection of pathogenic mtDNA alleles. The limited anticodon diversity of mitochondrial tRNAs forces m.7076G translation to rely on wobble pairing, unlike the Watson-Crick-Franklin pairing used for m.7076A. Mitochondrial ribosome profiling confirmed stalled translation of the m.7076G allele. Functional analyses demonstrated that the elevated translational and metabolic demands of short-lived effector T cells (SLECs) amplify dependence on MT-CO1, driving this selective pressure. These findings suggest that synonymous variants can alter codon syntax, impacting mitochondrial physiology in a cell type-specific manner.

Proceedings of the National Academy of SciencesVol. 122(30)
Boston Children's Hospital (US), Memorial Sloan Kettering Cancer Center (US), Harvard University (US), Illumina (United States) (US), Baylor College of Medicine (US), Max Delbrück Center (DE), Heidelberg University (DE), Infectious Disease Consultants (US), Parker Institute for Cancer Immunotherapy (US), Neurological Research Institute (US), Helmholtz Institute for RNA-based Infection Research (DE), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), Texas Children's Hospital (US), Texas Center for Infectious Disease (US), Freie Universität Berlin (DE), Heidelberg University (US), Stanford University (US)
Cancer Research Institute, Parker Institute for Cancer Immunotherapy, Deutsche Forschungsgemeinschaft, National Institutes of Health, National Cancer Institute
Life in Land
Openalex Percentile: Top 11%
Single-cell and spatial transcriptomics
2.42
DOIOpen Access PDFOpenAlex
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