T cell differentiation drives the negative selection of pathogenic mitochondrial DNA variants.
Journal
Life science alliance
ISSN: 2575-1077
Titre abrégé: Life Sci Alliance
Pays: United States
ID NLM: 101728869
Informations de publication
Date de publication:
11 2023
11 2023
Historique:
received:
13
07
2023
revised:
08
08
2023
accepted:
09
08
2023
medline:
4
9
2023
pubmed:
1
9
2023
entrez:
31
8
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37652671
pii: 6/11/e202302271
doi: 10.26508/lsa.202302271
pmc: PMC10471888
pii:
doi:
Substances chimiques
DNA, Mitochondrial
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 204709/Z/16/Z
Pays : United Kingdom
Organisme : Medical Research Council
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 203105/Z/16/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 219562/Z/19Z
Pays : United Kingdom
Informations de copyright
© 2023 Franklin et al.
Références
Ann Neurol. 1992 Apr;31(4):391-8
pubmed: 1586140
Ann Neurol. 2015 May;77(5):753-9
pubmed: 25652200
Nat Immunol. 2020 Sep;21(9):1022-1033
pubmed: 32661364
Bioinformatics. 2009 Sep 1;25(17):2283-5
pubmed: 19542151
Am J Hum Genet. 2008 Feb;82(2):333-43
pubmed: 18252214
Adv Nutr. 2016 Jul 15;7(4):798S-805S
pubmed: 27422517
Biochem Int. 1990 Aug;21(5):789-96
pubmed: 2124116
BBA Clin. 2016 Apr 29;6:19-24
pubmed: 27331024
Int Rev Immunol. 2016 Nov;35(6):477-488
pubmed: 26606199
Nature. 1990 Dec 13;348(6302):651-3
pubmed: 2102678
Clin Genet. 2018 Apr;93(4):925-928
pubmed: 29266179
J Med Genet. 2007 Jan;44(1):69-74
pubmed: 16950816
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
FEBS Lett. 2021 Apr;595(8):1003-1024
pubmed: 33513266
EMBO Mol Med. 2018 Jun;10(6):
pubmed: 29735722
Ann Clin Transl Neurol. 2018 Feb 07;5(3):333-345
pubmed: 29560378
Nat Commun. 2021 Nov 4;12(1):6409
pubmed: 34737295
Cell. 1990 Jun 15;61(6):931-7
pubmed: 2112427
Nat Rev Genet. 2015 Sep;16(9):530-42
pubmed: 26281784
Oncotarget. 2017 Sep 1;8(43):73627-73639
pubmed: 29088732
Cell Metab. 2017 Jun 6;25(6):1254-1268.e7
pubmed: 28591633
Immunity. 2012 Jan 27;36(1):68-78
pubmed: 22206904
Am J Hum Genet. 2001 Jan;68(1):238-40
pubmed: 11085913
Biochem J. 2003 Mar 15;370(Pt 3):751-62
pubmed: 12467494
Mitochondrion. 2007 Dec;7(6):374-85
pubmed: 17890163
N Engl J Med. 2020 Oct 15;383(16):1556-1563
pubmed: 32786181
Proc Natl Acad Sci U S A. 2013 Sep 17;110(38):E3622-30
pubmed: 24003133
Nat Commun. 2021 Dec 6;12(1):6997
pubmed: 34873176
Nature. 2019 Sep;573(7773):E2
pubmed: 31447485
J Neurol Sci. 1998 Nov 26;161(1):36-9
pubmed: 9879679
Int Immunol. 1999 Jul;11(7):1027-33
pubmed: 10383934
Biochem J. 1996 Sep 1;318 ( Pt 2):401-7
pubmed: 8809026
PLoS Biol. 2019 Oct 29;17(10):e3000383
pubmed: 31661488
Bioinformatics. 2011 Aug 1;27(15):2156-8
pubmed: 21653522
J Neurol. 2016 May;263(5):961-972
pubmed: 26995359
Biochim Biophys Acta. 2008 May;1782(5):317-25
pubmed: 18319067
Nature. 2017 Dec 21;552(7685):362-367
pubmed: 29236685
Open Biol. 2020 May;10(5):200061
pubmed: 32428418
J Neurol. 2014 Mar;261(3):504-10
pubmed: 24375076
Proc Natl Acad Sci U S A. 1992 May 15;89(10):4221-5
pubmed: 1584755
Nat Rev Immunol. 2005 Nov;5(11):844-52
pubmed: 16239903
J Immunol. 2006 Jul 15;177(2):852-62
pubmed: 16818739
Neurology. 2006 Jun 27;66(12):1932-4
pubmed: 16801664
Bioinformatics. 2009 Aug 15;25(16):2078-9
pubmed: 19505943
Immunity. 2018 Feb 20;48(2):202-213
pubmed: 29466753
Cell Rep. 2016 Dec 20;17(12):3142-3152
pubmed: 28009285
Mol Biol Evol. 2022 May 3;39(5):
pubmed: 35482398
J Inherit Metab Dis. 2012 Nov;35(6):1059-69
pubmed: 22403016
J Allergy Clin Immunol Pract. 2014 Jul-Aug;2(4):465-468, 468.e1
pubmed: 25017538
Am J Hum Genet. 1992 Dec;51(6):1187-200
pubmed: 1334369