Mitochondrial dysfunction-induced high hCG associated with development of fetal growth restriction and pre-eclampsia with fetal growth restriction

Ryo Kiyokoba,Takahiro Toshima,Dongchon Kang,Kiyoko Kato,Yasuyuki Fujita,Shigehiro Tsukahara,Mikako Yagi,Takeshi Uchiumi

doi:10.1038/s41598-022-07893-y

Ryo Kiyokoba, Takahiro Toshima + Show 6 more

Open Access

https://doi.org/10.1038/s41598-022-07893-y

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Journal: Scientific Reports	Publication Date: Mar 8, 2022
Citations: 8	License type: open-access

Affiliation: Kyushu University

Abstract

Fetal growth restriction (FGR) and pre-eclampsia with fetal growth restriction (PE/FGR) are high-risk perinatal diseases that may involve high levels of human chorionic gonadotropin (hCG) and mitochondrial dysfunction. However, little is known about how these factors affect placental function. We investigated how mitochondrial dysfunction and high hCG expression affected placental function in unexplained FGR and PE/FGR. We observed elevated expression of hCGβ and growth differentiation factor 15 mRNA and protein levels in the placenta with both diseases. Likewise, antiangiogenic factors, such as Ang2, IP10, sFlt1, IL8, IL1B, and TNFα, were also upregulated at the mRNA level. In addition, the expression of COXI and COXII which encoded by mitochondrial DNA were significantly decreased in both diseases, suggesting that mitochondrial translation was impaired. Treatment with hCG increased Ang2, IP10, IL8, and TNFα mRNA levels in a dose-dependent manner via the p38 and JNK pathways. Mitochondrial translation inhibitors increased hCGβ expression through stabilization of HIF1α, and increased IL8 and TNFα mRNA expression. These results revealed that high expression of hCG due to mitochondrial translational dysfunction plays an important role in the pathogenesis of FGR and PE/FGR.

Highlights

Fetal growth restriction (FGR) and pre-eclampsia with fetal growth restriction (PE/FGR) are highrisk perinatal diseases that may involve high levels of human chorionic gonadotropin and mitochondrial dysfunction
Expression of hCGβ mRNA was elevated in FGR and PE/FGR samples (Fig. 1g), suggesting that the high human chorionic gonadotropin (hCG) expression was transcriptionally regulated in placentas from patients showing FGR and PE/FGR
Elevated expression levels of voltage-dependent anion channel (VDAC) and translocase of outer mitochondrial membrane 20 (TOM20) proteins were observed in placentas from patients with FGR, but there were no changes in expression in samples associated with PE/FGR, indicating that mitochondrial translational dysfunction was not caused by reduced mitochondrial number or mass (Fig. 4a,b,h,i). These results suggest that the high expression of hCG and mitochondrial translational dysfunction may play an important role in the pathogenesis of FGR and PE/FGR (Figs. 1, 2, 3, 4, and Supplementary Fig. 1–3)

Summary

Introduction

Fetal growth restriction (FGR) and pre-eclampsia with fetal growth restriction (PE/FGR) are highrisk perinatal diseases that may involve high levels of human chorionic gonadotropin (hCG) and mitochondrial dysfunction. Mitochondrial translation inhibitors increased hCGβ expression through stabilization of HIF1α, and increased IL8 and TNFα mRNA expression These results revealed that high expression of hCG due to mitochondrial translational dysfunction plays an important role in the pathogenesis of FGR and PE/FGR. Fetal growth restriction (FGR) is the failure of a fetus to achieve its genetic growth potential in utero and is associated with a significant risk factor of preterm birth, neonatal death, and stillbirth It is a major cause of infant mortality and morbidity after preterm b irth[1]. The primary cause of FGR and PE has been reported to be ‘placental insufficiency’ This means that the fetus does not get enough nutrients and oxygen and is affected by a variety of factors, including changes in maternal or fetal blood flow, decreased oxygen, and poor adaptation to high oxygen and n utrients[3].

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