Cell type-specific purifying selection of synonymous mitochondrial DNA variation

• 成果类型: Article
• 署名作者: Lareau, Caleb A.; Maschmeyer, Patrick; Yin, Yajie; Gutierrez, Jacob C.; Dhindsa, Ryan S.; Burrer, Anne - Sophie Gribling -; Zielinski, Sebastian; Hsieh, Yu - Hsin; Nitsch, Lena; Dimitrova, Veronika; Nalbant, Benan; Buquicchio, Frank A.; Abay, Tsion; Stickels, Robert R.; Ulirsch, Jacob C.; Yan, Patrick; Wang, Fangyi; Miao, Zhuang; Sandor, Katalin; Daniel, Bence; Liu, Vincent; Mendez, Paul L.; Knaus, Petra; Meyer, Manpreet; Greenleaf, William J.; Kundaje, Anshul; Smyth, Redmond P.; Munschauer, Mathias; Ludwig, Leif S.; Satpathy, Ansuman T.
• 署名单位: Memorial Sloan Kettering Cancer Center; Stanford University; Humboldt University of Berlin; Free University of Berlin; Charite Universitatsmedizin Berlin; Berlin Institute of Health; Helmholtz Association; Max Delbruck Center for Molecular Medicine; Baylor College of Medicine; Baylor College of Medicine; Baylor College Medical Hospital; Baylor College of Medicine; Helmholtz Association; Helmholtz-Center for Infection Research; Free University of Berlin; Harvard University; Harvard Medical School; Stanford University; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard Medical School; Stanford University; Ruprecht Karls University Heidelberg
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12881
• DOI: 10.1073/pnas.2505704122
• 发表日期: 2025-07-29
• 关键词: mutations; DYNAMICS; patient

摘要

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+ 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.