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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (30)
Caleb A. Lareau
Patrick Maschmeyer
Berlin Institute of Health at Charité—Universitätsmedizin Berlin
Yajie Yin
Department of Pathology, Stanford University
Jacob C. Gutierrez
Ryan S. Dhindsa
Anne-Sophie Gribling-Burrer
Sebastian Zielinski
Helmholtz Institute for RNA-based Infection Research, Helmholtz-Center for Infection Research
Yu-Hsin Hsieh
Berlin Institute of Health at Charité—Universitätsmedizin Berlin
Lena Nitsch
Veronika Dimitrova
Berlin Institute of Health at Charité—Universitätsmedizin Berlin
Benan Nalbant
Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center
Frank A. Buquicchio
Department of Pathology, Stanford University
Tsion Abay
Department of Pathology, Stanford University
Robert R. Stickels
Department of Pathology, Stanford University
Jacob C. Ulirsch
Patrick Yan
Department of Pathology, Stanford University
Fangyi Wang
Department of Pathology, Stanford University
Zhuang Miao
Katalin Sandor
Department of Pathology, Stanford University
Bence Daniel
Department of Pathology, Stanford University
Vincent Liu
Department of Pathology, Stanford University
Paul L. Mendez
Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin
Petra Knaus
Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin
Manpreet Meyer
Berlin Institute of Health at Charité—Universitätsmedizin Berlin
William J. Greenleaf
Anshul Kundaje
Redmond P. Smyth
Mathias Munschauer
Helmholtz Institute for RNA-based Infection Research, Helmholtz-Center for Infection Research
Leif S. Ludwig
Ansuman T. Satpathy