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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.
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
URL: https://doi.org/10.26508/lsa.202302271
DOI: 10.26508/lsa.202302271
Data Access Statement: Underlying data and supporting analytic code for the manuscript can be accessed via https://github.com/sarahjpickett/mtDNA_variant_blood_cells.
PubMed id: 37652671
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