Paper

Mitochondrial citrate metabolism and efflux regulates trophoblast differentiation

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

2023

Overview

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.Competing Interest StatementP.A.C. has served as an external consultant for Pfizer, Inc., Abbott Laboratories, Janssen Research & Development, and Juvenesence.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Acetic acid / Acetylation / Cell culture / Cell differentiation / Citric acid / CRISPR / Developmental Biology / Gene expression / Histones / Intermediates / Ketoglutaric acid / Metabolism / Metabolomics / Mitochondria / Supplements / Tricarboxylic acid cycle / Trophoblasts