Duncan NRI Faculty and Staff Publications

Language

English

Publication Date

7-29-2025

Journal

Proceedings of the National Academy of Sciences of the United States of America

DOI

10.1073/pnas.2505704122

PMID

40705423

PMCID

PMC12318227

PubMedCentral® Posted Date

7-24-2025

PubMedCentral® Full Text Version

Post-print

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+ 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

Humans, DNA, Mitochondrial, Electron Transport Complex IV, Selection, Genetic, Mitochondria, CD8-Positive T-Lymphocytes, Genetic Variation, Alleles, RNA, Transfer, immunology, mitochondria, selection, single-cell

Published Open-Access

yes

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