The Endoplasmic Reticulum Stress of Placental Impoverishment

Abstract

If mitochondria are the power packs of the cell, then the endoplasmic reticulum (ER) is the industrial complex, where secretory proteins and other factors are synthesized. Disruption of this organelle, such as by ER stress, can wreak havoc not just on the individual cell but also on the organism as a whole. One such example of this is the ER stress that occurs during the placental stress of intrauterine growth restriction. In this issue of The American Journal of Pathology, Yung and colleagues 1 publish a landmark paper in which the role of the ER in placental stress and its associated clinical syndromes is elucidated. To understand fully the importance of the ER in intrauterine growth restriction, one must appreciate the intricacies of ER function.Nearly all eukaryotic cells contain the ER, a labyrinthine network of interlinked flattened sacs with a continuous cavity that is separated from the cytoplasm by the ER membrane. The ER's specialized intracellular environment is very high in Ca2 ϩ and oxidizing potential. 2 Ribosomes transiently attached to the outside of the membrane are the defining feature of the rough ER. The smooth ER, on the other hand, is devoid of ribosomes but is rich in enzymes that synthesize lipids and membrane phospholipids and participates in steroid synthesis, in specific cell types. Rough and smooth ER are interconnected, not physically discrete, and the relative proportion of each quickly changes.As each new peptide is synthesized by the ribosomes of the rough ER, the elongating amino acid chain is extruded into the ER lumen; subsequently whereas the ribosome detaches once its job is done. The naïve peptide enters the ER and folds spontaneously to minimize exposure of hydrophobic areas. Successful protein folding requires a controlled environment of substrates that include glucose to supply energy and calcium and redox buffers that maintain the oxidizing environment required for disulfide bond formation.2 Further conformational ad-

Regulation of amino acid transporter trafficking by mTORC1 in primary human trophoblast cells is mediated by the ubiquitin ligase Nedd4-2

“…Third, Nedd4-2 silencing prevented the decrease in System A and L activity in response to mTORC1 inhibition. These findings are consistent with the model that inhibition of placental mTORC1 in human IUGR [20, 21] increases the ubiquitination of specific System A and L amino acid transporter isoforms mediated by activation of Nedd4-2 (Fig 7), resulting in decreased placental amino acid transport and fetal amino acid availability [5–8]. …”

“…Both placental mTORC1 and mTORC2 activity is decreased in human IUGR [20, 21] as well as in animal models of IUGR such as low protein diet in the rat [22]. In addition, maternal nutrient restriction in the baboon inhibits placental mTOR signaling [23].…”

Mechanistic target of rapamycin (mTOR) regulates trophoblast folate uptake by modulating the cell surface expression of FR-α and the RFC

“…Placental mTOR signaling has been reported to be inhibited in human intrauterine growth restriction444546 and in animal models of maternal undernutrition4748. The findings in the present study therefore raise the possibility that placental mTOR mediated dysregulation of placental folate transport plays a role in the development of abnormal fetal growth.…”

The emerging role of mTORC1 signaling in placental nutrient-sensing

“…The placental AAR pathway has been reported to be activated in a rat model of maternal protein restriction (4). Furthermore, eIF2α phosphorylation is increased in IUGR placentas (5)3 however, whether this is mediated by GCN2 kinase or by activation of protein kinase-like endoplasmic reticulum kinase (PERK) in the unfolded protein response (UPR) pathway (5) is unknown.…”