Mitochondrial Ca2+ Overload Leads to Mitochondrial Oxidative Stress and Delayed Meiotic Resumption in Mouse Oocytes

Overweight or obese women seeking pregnancy is becoming increasingly common. Human maternal obesity gives rise to detrimental effects during reproduction. Emerging evidence has shown that these abnormities are likely attributed to oocyte quality. Oxidative stress induces poor oocyte conditions, but...

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Main Authors: Luyao Zhang, Zichuan Wang, Tengfei Lu, Lin Meng, Yan Luo, Xiangwei Fu, Yunpeng Hou
Format: Article
Language:English
Published: Frontiers Media S.A. 2020-12-01
Series:Frontiers in Cell and Developmental Biology
Subjects:
Online Access:https://www.frontiersin.org/articles/10.3389/fcell.2020.580876/full
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author Luyao Zhang
Zichuan Wang
Tengfei Lu
Lin Meng
Yan Luo
Xiangwei Fu
Yunpeng Hou
author_facet Luyao Zhang
Zichuan Wang
Tengfei Lu
Lin Meng
Yan Luo
Xiangwei Fu
Yunpeng Hou
author_sort Luyao Zhang
collection DOAJ
description Overweight or obese women seeking pregnancy is becoming increasingly common. Human maternal obesity gives rise to detrimental effects during reproduction. Emerging evidence has shown that these abnormities are likely attributed to oocyte quality. Oxidative stress induces poor oocyte conditions, but whether mitochondrial calcium homeostasis plays a key role in oocyte status remains unresolved. Here, we established a mitochondrial Ca2+ overload model in mouse oocytes. Knockdown gatekeepers of the mitochondrial Ca2+ uniporters Micu1 and Micu2 as well as the mitochondrial sodium calcium exchanger NCLX in oocytes both increased oocytes mitochondrial Ca2+ concentration. The overload of mitochondria Ca2+ in oocytes impaired mitochondrial function, leaded to oxidative stress, and changed protein kinase A (PKA) signaling associated gene expression as well as delayed meiotic resumption. Using this model, we aimed to determine the mechanism of delayed meiosis caused by mitochondrial Ca2+ overload, and whether oocyte-specific inhibition of mitochondrial Ca2+ influx could improve the reproductive abnormalities seen within obesity. Germinal vesicle breakdown stage (GVBD) and extrusion of first polar body (PB1) are two indicators of meiosis maturation. As expected, the percentage of oocytes that successfully progress to the germinal vesicle breakdown stage and extrude the first polar body during in vitro culture was increased significantly, and the expression of PKA signaling genes and mitochondrial function recovered after appropriate mitochondrial Ca2+ regulation. Additionally, some indicators of mitochondrial performance—such as adenosine triphosphate (ATP) and reactive oxygen species (ROS) levels and mitochondrial membrane potential—recovered to normal. These results suggest that the regulation of mitochondrial Ca2+ uptake in mouse oocytes has a significant role during oocyte maturation as well as PKA signaling and that proper mitochondrial Ca2+ reductions in obese oocytes can recover mitochondrial performance and improve obesity-associated oocyte quality.
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spelling doaj.art-50377af9e4544788aa1e1b08c0169e0e2022-12-21T22:33:59ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2020-12-01810.3389/fcell.2020.580876580876Mitochondrial Ca2+ Overload Leads to Mitochondrial Oxidative Stress and Delayed Meiotic Resumption in Mouse OocytesLuyao Zhang0Zichuan Wang1Tengfei Lu2Lin Meng3Yan Luo4Xiangwei Fu5Yunpeng Hou6State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, ChinaState Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, ChinaState Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, ChinaState Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, ChinaState Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, ChinaKey Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture and National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, ChinaState Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, ChinaOverweight or obese women seeking pregnancy is becoming increasingly common. Human maternal obesity gives rise to detrimental effects during reproduction. Emerging evidence has shown that these abnormities are likely attributed to oocyte quality. Oxidative stress induces poor oocyte conditions, but whether mitochondrial calcium homeostasis plays a key role in oocyte status remains unresolved. Here, we established a mitochondrial Ca2+ overload model in mouse oocytes. Knockdown gatekeepers of the mitochondrial Ca2+ uniporters Micu1 and Micu2 as well as the mitochondrial sodium calcium exchanger NCLX in oocytes both increased oocytes mitochondrial Ca2+ concentration. The overload of mitochondria Ca2+ in oocytes impaired mitochondrial function, leaded to oxidative stress, and changed protein kinase A (PKA) signaling associated gene expression as well as delayed meiotic resumption. Using this model, we aimed to determine the mechanism of delayed meiosis caused by mitochondrial Ca2+ overload, and whether oocyte-specific inhibition of mitochondrial Ca2+ influx could improve the reproductive abnormalities seen within obesity. Germinal vesicle breakdown stage (GVBD) and extrusion of first polar body (PB1) are two indicators of meiosis maturation. As expected, the percentage of oocytes that successfully progress to the germinal vesicle breakdown stage and extrude the first polar body during in vitro culture was increased significantly, and the expression of PKA signaling genes and mitochondrial function recovered after appropriate mitochondrial Ca2+ regulation. Additionally, some indicators of mitochondrial performance—such as adenosine triphosphate (ATP) and reactive oxygen species (ROS) levels and mitochondrial membrane potential—recovered to normal. These results suggest that the regulation of mitochondrial Ca2+ uptake in mouse oocytes has a significant role during oocyte maturation as well as PKA signaling and that proper mitochondrial Ca2+ reductions in obese oocytes can recover mitochondrial performance and improve obesity-associated oocyte quality.https://www.frontiersin.org/articles/10.3389/fcell.2020.580876/fullmitochondriacalcium overloadoocytesmeiosisobesity
spellingShingle Luyao Zhang
Zichuan Wang
Tengfei Lu
Lin Meng
Yan Luo
Xiangwei Fu
Yunpeng Hou
Mitochondrial Ca2+ Overload Leads to Mitochondrial Oxidative Stress and Delayed Meiotic Resumption in Mouse Oocytes
Frontiers in Cell and Developmental Biology
mitochondria
calcium overload
oocytes
meiosis
obesity
title Mitochondrial Ca2+ Overload Leads to Mitochondrial Oxidative Stress and Delayed Meiotic Resumption in Mouse Oocytes
title_full Mitochondrial Ca2+ Overload Leads to Mitochondrial Oxidative Stress and Delayed Meiotic Resumption in Mouse Oocytes
title_fullStr Mitochondrial Ca2+ Overload Leads to Mitochondrial Oxidative Stress and Delayed Meiotic Resumption in Mouse Oocytes
title_full_unstemmed Mitochondrial Ca2+ Overload Leads to Mitochondrial Oxidative Stress and Delayed Meiotic Resumption in Mouse Oocytes
title_short Mitochondrial Ca2+ Overload Leads to Mitochondrial Oxidative Stress and Delayed Meiotic Resumption in Mouse Oocytes
title_sort mitochondrial ca2 overload leads to mitochondrial oxidative stress and delayed meiotic resumption in mouse oocytes
topic mitochondria
calcium overload
oocytes
meiosis
obesity
url https://www.frontiersin.org/articles/10.3389/fcell.2020.580876/full
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