Proc Natl Acad Sci U S A. 2025 Jul 29. 122(30): e2505704122
Caleb A Lareau,
Patrick Maschmeyer,
Yajie Yin,
Jacob C Gutierrez,
Ryan S Dhindsa,
Anne-Sophie Gribling-Burrer,
Sebastian Zielinski,
Yu-Hsin Hsieh,
Lena Nitsch,
Veronika Dimitrova,
Benan Nalbant,
Frank A Buquicchio,
Tsion Abay,
Robert R Stickels,
Jacob C Ulirsch,
Patrick Yan,
Fangyi Wang,
Zhuang Miao,
Katalin Sandor,
Bence Daniel,
Vincent Liu,
Paul L Mendez,
Petra Knaus,
Manpreet Meyer,
William J Greenleaf,
Anshul Kundaje,
Redmond P Smyth,
Mathias Munschauer,
Leif S Ludwig,
Ansuman T Satpathy.
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.
Keywords: immunology; mitochondria; selection; single-cell