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

ABSTRACT: 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.

SUBMITTER: Franklin IG

PROVIDER: S-EPMC10471888 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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

Franklin Imogen G IG Milne Paul P Childs Jordan J Boggan Róisín M RM Barrow Isabel I Lawless Conor C Gorman Gráinne S GS Ng Yi Shiau YS Collin Matthew M Russell Oliver M OM Pickett Sarah J SJ

Life science alliance 20230831 11

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 individu ...[more]

PMID: 37652671

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Project description:Study questionDoes selection for mtDNA mutations occur in human oocytes?Summary answerWe provide statistical evidence in favor of the existence of purifying selection for mtDNA mutations in human oocytes acting between the expulsion of the first and second polar bodies (PBs).What is known alreadySeveral lines of evidence in Metazoa, including humans, indicate that variation within the germline of mitochondrial genomes is under purifying selection. The presence of this internal selection filter in the germline has important consequences for the evolutionary trajectory of mtDNA. However, the nature and localization of this internal filter are still unclear while several hypotheses are proposed in the literature.Study design, size, durationIn this study, 60 mitochondrial genomes were sequenced from 17 sets of oocytes, first and second PBs, and peripheral blood taken from nine women between 38 and 43 years of age.Participants/materials, setting, methodsWhole genome amplification was performed only on the single cell samples and Sanger sequencing was performed on amplicons. The comparison of variant profiles between first and second PB sequences showed no difference in substitution rates but displayed instead a sharp difference in pathogenicity scores of protein-coding sequences using three different metrics (MutPred, Polyphen and SNPs&GO).Main results and the role of chanceUnlike the first, second PBs showed no significant differences in pathogenic scores with blood and oocyte sequences. This suggests that a filtering mechanism for disadvantageous variants operates during oocyte development between the expulsion of the first and second PB.Large scale dataN/A.Limitations, reasons for cautionThe sample size is small and further studies are needed before this approach can be used in clinical practice. Studies on a model organism would allow the sample size to be increased.Wider implications of the findingsThis work opens the way to the study of the correlation between mtDNA mutations, mitochondrial capacity and viability of oocytes.Study funding/competing interest(s)This work was supported by a SISMER grant. Laboratory facilities and skills were freely provided by SISMER, and by the Alma Mater Studiorum, University of Bologna. The authors have no conflict of interest to disclose.

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

Publications

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

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