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mTOR regulation of trophoblast transcriptome and mitochondrial respiration (1159.1)
Author(s) -
Rosario Fredrick,
Cox Laura,
Lange Kenneth,
Muralimanoharan Subha,
Myatt Leslie,
Powell Theresa,
Jansson Thomas
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1159.1
Subject(s) - mtorc1 , mtorc2 , pi3k/akt/mtor pathway , microbiology and biotechnology , transcriptome , biology , mitochondrion , oxidative phosphorylation , mechanistic target of rapamycin , downregulation and upregulation , p70 s6 kinase 1 , signal transduction , biochemistry , gene expression , gene
The role of mechanistic target of rapamycin complex 1 (mTORC1) and mTORC2 in regulating the function of the syncytiotrophoblast, the placental transporting epithelium, is largely unknown. We hypothesized that silencing of mTORC1 in primary human trophoblast (PHT) cells (a) down‐regulates key genes involved in oxidative phosphorylation and ribosome synthesis and (b) inhibits mitochondrial respiration. We silenced raptor (mTORC1 inhibition), rictor (mTORC2 inhibition) or deptor (mTORC1/2 activation) in cultured term PHT cells and performed transcriptome profiling and measured mitochondrial respiration. Inhibition of mTORC1 resulted in a highly coordinated transcriptional response including downregulation of genes in networks related to oxidative phosphorylation, ribosome and lipid biosynthesis whereas inhibition of mTORC2 had no effect on these pathways. Inhibition of mTORC1, but not mTORC2, decreased mitochondrial basal/maximal respiration, ATP coupling, reserve capacity and proton leak, whereas activation of mTORC1/2 had the opposite effect. In conclusion, mTORC1 and 2 differentially regulates the trophoblast transcriptome and mTORC1 is a positive regulator of mitochondrial respiratory function. Placental mTOR signaling is inhibited in fetal growth restriction, which may impair mitochondrial respiration and contribute to placental insufficiency in this pregnancy complication. Grant Funding Source : NIH HD068370