The spatial expression of mTORC2-AKT-IP3R signal pathway in mitochondrial combination of endoplasmic reticulum of maternal fetal interface trophoblast in intrahepatic cholestasis of pregnancy

Yaqian Li; Daijuan Chen; Jinfeng Xu; Xiaodong Wang; Fan Zhou

doi:10.1515/jpm-2022-0570

Article

The spatial expression of mTORC2-AKT-IP3R signal pathway in mitochondrial combination of endoplasmic reticulum of maternal fetal interface trophoblast in intrahepatic cholestasis of pregnancy

Yaqian Li , Daijuan Chen , Jinfeng Xu , Xiaodong Wang and Fan Zhou

Published/Copyright: April 28, 2023

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From the journal Journal of Perinatal Medicine Volume 51 Issue 8

Abstract

Objectives

Intrahepatic cholestasis of pregnancy (ICP) is complicated by adverse fetal outcomes and even fetal death, the mechanism remains unclear. This study aims at evaluating the differential expression of mTORC2-AKT-IP3R signaling pathway, which accurately regulate Ca²⁺ transfer across mitochondria-associated membranes (MAMs) and determine the stress intensity experienced by endoplasmic reticulum (ER) and mitochondria, in patients diagnosed with ICP.

Methods

We combined western blot analysis and placental immunofluorescence co-localization detection to assess the expression and co-localization of the mTORC2-AKT-IP3R signaling pathway in severe (maternal total bile acid (TBA) levels ≥40 μmol/L) and mild (maternal TBA 10–40 μmol/L) ICP.

Results

Compared with the control and mild ICP groups, phosphorylated protein kinase B (p-AKT) levels were significantly upregulated in the severe ICP group. Placental Rictor levels were lower in the mild ICP group than in the control group and were further downregulated in the severe ICP group. IP3R3 and p-IP3R3 levels were lower in placentas in the severe ICP group than in those in the mild ICP and control groups. Moreover, the co-localization of IP3R3 and p-AKT in patients in the mild and severe ICP groups was significantly elevated compared with that in patients in the control group.

Conclusions

In patients with severe ICP, limited expression of Rictor and elevated p-AKT levels would suppress IP3R3/p-IP3R3 levels in MAMs. This inhibition might influence the transportation of Ca²⁺ from the ER to the mitochondria, thus weaken the stress adaptation associated with MAMs. Our results reveal the possible pathophysiological mechanism of adverse fetal outcomes in ICP.

Keywords: bile acid; calcium; intrahepatic cholestasis of pregnancy; mitochondria-associated membranes; placenta; stress

Corresponding author: Fan Zhou, Department of Medical Genetics/Prenatal Diagnosis Center, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, P.R. China; and Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, No. 20 Remnin Nan Road, Chengdu, Sichuan 610041, P.R. China, E-mail: judyzhoufan@hotmail.com

Funding source: National Natural Science Foundation of China

Award Identifier / Grant number: 81801485

Research funding: This work was supported by the National Natural Science Foundation of China [grant number 81801485].
Author contributions: YQ Li: project development, data collection, data analysis; F Zhou: project development, data analysis, manuscript writing; DJ Chen: data collection, manuscript editing; JF Xu: data collection, manuscript editing; XD Wang: project development, data analysis, manuscript editing. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
Informed consent: Informed consent was obtained from all individuals included in this study.
Ethical approval: Approval from the West China Second University Hospital Institutional Review Board (IRB) was obtained prior to patient enrollment.

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Received: 2022-11-25

Accepted: 2023-04-05

Published Online: 2023-04-28

Published in Print: 2023-10-26

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Articles in the same Issue

https://doi.org/10.1515/jpm-2022-0570

Keywords for this article

bile acid; calcium; intrahepatic cholestasis of pregnancy; mitochondria-associated membranes; placenta; stress