Cell type–specific purifying selection of synonymous mitochondrial DNA variation Journal Article

   


Authors: Lareau, C. A.; Maschmeyer, P.; Yin, Y.; Gutierrez, J. C.; Dhindsa, R. S.; Gribling-Burrer, A. S.; Zielinski, S.; Hsieh, Y. H.; Nitsch, L.
Article Title: Cell type–specific purifying selection of synonymous mitochondrial DNA variation
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. © 2025 Elsevier B.V., All rights reserved.
Keywords: protein expression; human cell; genetics; flow cytometry; cd8+ t lymphocyte; cd8-positive t-lymphocytes; quality control; metabolism; allele; gene; gene expression; genotype; alleles; genetic variation; haplotype; immunology; blood sampling; western blotting; cell isolation; real time polymerase chain reaction; transfer rna; rna, transfer; bioinformatics; dna, mitochondrial; mitochondria; dna extraction; fluorescence activated cell sorting; mitochondrion; genetic selection; mitochondrial dna; memory t lymphocyte; selection; selection, genetic; transmission electron microscopy; cytochrome c oxidase; single cell analysis; single-cell; high throughput sequencing; electron transport complex iv; sanger sequencing; humans; human; article; gene editing; heteroplasmy; single cell rna seq; novaseq 6000; bd lsr fortessa x- 20 flow cytometer; bioanalyzer 2100 system; c1000 touch thermal cycler; cellranger atac count v2.0; cellranger v6.0; direct zol rna miniprep kit; dneasy blood and tissue kit; illumina novaseq x plus 10b; qubit dsdna hs assay kit; rna clean and concentrator kit; melas syndrome; mt co1 gene
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 122
Issue: 30
ISSN: 10916490
Publisher: Elsevier B.V.  
Date Published: 2025-01-01
Start Page: e2505704122
Language: English
DOI: 10.1073/pnas.2505704122
PUBMED: 40705423
PROVIDER: scopus
PMCID: PMC12318227
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-105012102809&doi=10.1073%2Fpnas.2505704122&partnerID=40&md5=80570190c1a7e247cbc20f78b66e3a3d
Notes: Article -- Source: Scopus
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