Mitochondrial citrate metabolism and efflux regulate BeWo differentiation.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
06 05 2023
06 05 2023
Historique:
received:
01
02
2023
accepted:
29
04
2023
medline:
8
5
2023
pubmed:
7
5
2023
entrez:
6
5
2023
Statut:
epublish
Résumé
Cytotrophoblasts fuse to form and renew syncytiotrophoblasts necessary to maintain placental health throughout gestation. During cytotrophoblast to syncytiotrophoblast differentiation, cells undergo regulated metabolic and transcriptional reprogramming. Mitochondria play a critical role in differentiation events in cellular systems, thus we hypothesized that mitochondrial metabolism played a central role in trophoblast differentiation. In this work, we employed static and stable isotope tracing untargeted metabolomics methods along with gene expression and histone acetylation studies in an established BeWo cell culture model of trophoblast differentiation. Differentiation was associated with increased abundance of the TCA cycle intermediates citrate and α-ketoglutarate. Citrate was preferentially exported from mitochondria in the undifferentiated state but was retained to a larger extent within mitochondria upon differentiation. Correspondingly, differentiation was associated with decreased expression of the mitochondrial citrate transporter (CIC). CRISPR/Cas9 disruption of the mitochondrial citrate carrier showed that CIC is required for biochemical differentiation of trophoblasts. Loss of CIC resulted in broad alterations in gene expression and histone acetylation. These gene expression changes were partially rescued through acetate supplementation. Taken together, these results highlight a central role for mitochondrial citrate metabolism in orchestrating histone acetylation and gene expression during trophoblast differentiation.
Identifiants
pubmed: 37149697
doi: 10.1038/s41598-023-34435-x
pii: 10.1038/s41598-023-34435-x
pmc: PMC10164164
doi:
Substances chimiques
Histones
0
Citrates
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7387Subventions
Organisme : NICHD NIH HHS
ID : K12 HD000849
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK104998
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK091538
Pays : United States
Organisme : NICHD NIH HHS
ID : R21 HD102770
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG069781
Pays : United States
Organisme : NIH HHS
ID : K12 HD000849
Pays : United States
Commentaires et corrections
Type : UpdateOf
Informations de copyright
© 2023. The Author(s).
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