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T cell differentiation drives the negative selection of pathogenic mitochondrial DNA variants

Lookup NU author(s): Imogen Franklin, Dr Paul Milne, Jordan Childs, Dr Roisin Boggan, Isabel Barrow, Dr Conor LawlessORCiD, Professor Grainne Gorman, Dr Yi NgORCiD, Professor Matthew CollinORCiD, Dr Oliver Russell, Dr Sarah PickettORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2023 Franklin et al. Pathogenic mitochondrial DNA (mtDNA) single-nucleotide variants are a common cause of adult mitochondrial disease. Levels of some variants decrease with age in blood. Given differing division rates, longevity, and energetic requirements within haematopoietic lineages, we hypothesised that cell-type-specific metabolic requirements drive this decline. We coupled cell-sorting with mtDNA sequencing to investigate mtDNA variant levels within progenitor, myeloid, and lymphoid lineages from 26 individuals harbouring one of two pathogenic mtDNA variants (m.3243A>G and m.8344A>G). For both variants, cells of the T cell lineage show an enhanced decline. High-throughput single-cell analysis revealed that decline is driven by increasing proportions of cells that have cleared the variant, following a hierarchy that follows the current orthodoxy of T cell differentiation and maturation. Furthermore, patients with pathogenic mtDNA variants have a lower proportion of T cells than controls, indicating a key role for mitochondrial function in T cell homeostasis. This work identifies the ability of T cell subtypes to selectively purify their mitochondrial genomes, and identifies pathogenic mtDNA variants as a new means to track blood cell differentiation status.

Publication metadata

Author(s): Franklin IG, Milne P, Childs J, Boggan RM, Barrow I, Lawless C, Gorman GS, Ng YS, Collin M, Russell OM, Pickett SJ

Publication type: Article

Publication status: Published

Journal: Life Science Alliance

Year: 2023

Volume: 6

Issue: 11

Print publication date: 01/11/2023

Online publication date: 31/08/2023

Acceptance date: 09/08/2023

Date deposited: 12/09/2023

ISSN (electronic): 2575-1077

Publisher: Life Science Alliance LLC


DOI: 10.26508/lsa.202302271

PubMed id: 37652671


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Funder referenceFunder name
204709/Z/16/ZWellcome Trust
203105/Z/16/ZWellcome Trust