Mitochondrial citrate metabolism and efflux regulates trophoblast 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:10.1101/2023.01.22.525071

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Mitochondrial citrate metabolism and efflux regulates trophoblast differentiation

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Mitochondrial citrate metabolism and efflux regulates trophoblast 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, …

bioRxiv : the preprint server for biology

01/22/2023

DOI: 10.1101/2023.01.22.525071

PMCID: PMC9882289

PMID: 36711862

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https://doi.org/10.1101/2023.01.22.525071View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

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 cell culture model of trophoblast differentiation. Trophoblast 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.

Details

Title: Subtitle: Mitochondrial citrate metabolism and efflux regulates trophoblast differentiation
Creators: 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
Resource Type: Preprint
Publication Details: bioRxiv : the preprint server for biology
DOI: 10.1101/2023.01.22.525071
PMID: 36711862
PMCID: PMC9882289
Grant note: R01 DK104998 / NIDDK NIH HHS
Language: English
Date posted: 01/22/2023
Academic Unit: Molecular Physiology and Biophysics; Fraternal Order of Eagles Diabetes Research Center
Record Identifier: 9984384313202771

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