Mitochondrial citrate metabolism and efflux regulate BeWo differentiation

Renee M Mahr; Snehalata Jena; Sereen K Nashif; Alisa B Nelson; Adam J Rauckhorst; Ferrol I Rome; Ryan D Sheldon; Curtis C Hughey; Patrycja Puchalska; Micah D Gearhart; Eric B Taylor; Peter A Crawford; Sarah A Wernimont

doi:10.1038/s41598-023-34435-x

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Mitochondrial citrate metabolism and efflux regulate BeWo differentiation

Journal article

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Peer reviewed

Mitochondrial citrate metabolism and efflux regulate BeWo differentiation

Renee M Mahr, Snehalata Jena, Sereen K Nashif, Alisa B Nelson, Adam J Rauckhorst, Ferrol I Rome, Ryan D Sheldon, Curtis C Hughey, Patrycja Puchalska, Micah D Gearhart, …

Scientific reports, Vol.13(1), 7387

05/06/2023

DOI: 10.1038/s41598-023-34435-x

PMCID: PMC10164164

PMID: 37149697

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Abstract

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.

Pregnancy

Cell Differentiation - genetics

Citrates - metabolism

Citrates - pharmacology

Female

Histones - metabolism

Humans

Mitochondria - metabolism

Placenta - metabolism

Trophoblasts - metabolism

Details

Title: Subtitle: Mitochondrial citrate metabolism and efflux regulate BeWo differentiation
Creators: Renee M Mahr - University of Minnesota
Snehalata Jena - University of Minnesota
Sereen K Nashif - University of Minnesota
Alisa B Nelson - University of Minnesota
Adam J Rauckhorst - University of Iowa
Ferrol I Rome - University of Minnesota
Ryan D Sheldon - University of Iowa
Curtis C Hughey - University of Minnesota
Patrycja Puchalska - University of Minnesota
Micah D Gearhart - University of Minnesota
Eric B Taylor - University of Iowa
Peter A Crawford - University of Minnesota
Sarah A Wernimont - University of Minnesota
Resource Type: Journal article
Publication Details: Scientific reports, Vol.13(1), 7387
DOI: 10.1038/s41598-023-34435-x
PMID: 37149697
PMCID: PMC10164164
NLM abbreviation: Sci Rep
eISSN: 2045-2322
Grant note: R01DK104998 / NIH HHS K12 HD000849 / NIH HHS R21HD102770 / NIH HHS
Language: English
Date published: 05/06/2023
Academic Unit: Molecular Physiology and Biophysics; Fraternal Order of Eagles Diabetes Research Center
Record Identifier: 9984403160202771

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