️ Episode 116: Cell Type–Specific Purifying Selection of Synonymous mtDNA Variation

In this episode of PaperCast Base by Base, we explore how a seemingly “silent” synonymous mitochondrial DNA mutation can shape immune cell fitness, revealing cell type–specific selection in human T cells and a mechanistic link to mitochondrial translation dynamics.

Study Highlights:
Using single-cell multiomics on peripheral blood from a healthy donor, the authors identify a mosaic synonymous variant in MT-CO1 (m.7076A>G, p.Gly391=) that is selectively depleted in CD8+ effector-memory T cells while remaining tolerated in other lineages. They show that the mutant codon forces wobble-dependent decoding by the limited mitochondrial tRNA pool, leading to ribosome stalling detected by mitochondrial ribosome profiling. Functional assays indicate that short-lived effector CD8+ T cells have heightened translational and metabolic demands, making them particularly sensitive to impaired MT-CO1 translation. Population-scale and evolutionary analyses suggest broader selective pressure favoring codon:anticodon pairings that optimize translation in mitochondria.

Conclusion:
Synonymous mitochondrial variants can be functionally consequential in a cell state–specific manner, with implications for immune biology, disease mechanisms, and the interpretation of mitochondrial genetics in both research and clinical contexts.

Reference:
Lareau CA, Maschmeyer P, Yin Y, et al. Cell type–specific purifying selection of synonymous mitochondrial DNA variation. Proceedings of the National Academy of Sciences. 2025;122(30):e2505704122. https://doi.org/10.1073/pnas.2505704122

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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Keywords: mitochondrial DNA; synonymous variant; CD8+ T cells; wobble translation; single-cell multiomics

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