Mechanistic Target of Rapamycin Complex 1 Promotes the Expression of Genes Encoding Electron Transport Chain Proteins and Stimulates Oxidative Phosphorylation in Primary Human Trophoblast Cells by Regulating Mitochondrial Biogenesis

Fredrick J. Rosario, Madhulika B. Gupta, Leslie Myatt, Theresa L. Powell, Jeremy P. Glenn, Laura Cox, Thomas Jansson

Research output: Contribution to journalArticle

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Abstract

Trophoblast oxidative phosphorylation provides energy for active transport and protein synthesis, which are critical placental functions influencing fetal growth and long-term health. The molecular mechanisms regulating trophoblast mitochondrial oxidative phosphorylation are largely unknown. We hypothesized that mechanistic Target of Rapamycin Complex 1 (mTORC1) is a positive regulator of key genes encoding Electron Transport Chain (ETC) proteins and stimulates oxidative phosphorylation in trophoblast and that ETC protein expression is down-regulated in placentas of infants with intrauterine growth restriction (IUGR). We silenced raptor (mTORC1 inhibition), rictor (mTORC2 inhibition) or DEPTOR (mTORC1/2 activation) in cultured term primary human trophoblast (PHT) cells. mTORC1 inhibition caused a coordinated down-regulation of 18 genes encoding ETC proteins representing all ETC complexes. Inhibition of mTORC1, but not mTORC2, decreased protein expression of ETC complexes I–IV, mitochondrial basal, ATP coupled and maximal respiration, reserve capacity and proton leak, whereas activation of mTORC1 had the opposite effects. Moreover, placental protein expression of ETC complexes was decreased and positively correlated to mTOR signaling activity in IUGR. By controlling trophoblast ATP production, mTORC1 links nutrient and O2 availability and growth factor signaling to placental function and fetal growth. Reduced placental mTOR activity may impair mitochondrial respiration and contribute to placental insufficiency in IUGR pregnancies.

Original languageEnglish (US)
Article number246
JournalScientific Reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

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Oxidative Phosphorylation
Trophoblasts
Organelle Biogenesis
Electron Transport
Carrier Proteins
Gene Expression
Fetal Development
Electron Transport Chain Complex Proteins
Respiration
Growth
Adenosine Triphosphate
Raptors
Placental Insufficiency
Pregnancy Proteins
Active Biological Transport
Regulator Genes
mechanistic target of rapamycin complex 1
Placenta
Protons
Intercellular Signaling Peptides and Proteins

ASJC Scopus subject areas

  • General

Cite this

Mechanistic Target of Rapamycin Complex 1 Promotes the Expression of Genes Encoding Electron Transport Chain Proteins and Stimulates Oxidative Phosphorylation in Primary Human Trophoblast Cells by Regulating Mitochondrial Biogenesis. / Rosario, Fredrick J.; Gupta, Madhulika B.; Myatt, Leslie; Powell, Theresa L.; Glenn, Jeremy P.; Cox, Laura; Jansson, Thomas.

In: Scientific Reports, Vol. 9, No. 1, 246, 01.12.2019.

Research output: Contribution to journalArticle

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