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Cell-Specific Paired Interrogation of the Mouse Ovarian Epigenome and Transcriptome

Cell-Specific Paired Interrogation of the Mouse Ovarian Epigenome and Transcriptome

Published on: February 24, 2023

The Immp2l Mutation Causes Ovarian Aging Through ROS-Wnt/β-Catenin-Estrogen Pathway: Preventive Effect of Melatonin

Qing He¹, Lifang Gu¹, Qingyin Lin¹

¹Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, Department of Pathology, Ningxia Key Laboratory of Cerebrocranial Diseases, Incubation Base of National Key Laboratory, Department of Center for Reproductive Medicine, General Hospital, Ningxia Medical University, Yinchuan, Ningxia, P.R. China.

|July 12, 2020

Abstract:

Mitochondria play important roles in ovarian follicle development. Mitochondrial dysfunction, including mitochondrial gene deficiency, impairs ovarian development. Here, we explored the role and mechanism of mitochondrial inner membrane gene Immp2l in ovarian follicle growth and development. Our results revealed that female Immp2l-/- mice were infertile, whereas Immp2l+/- mice were normal. Body and ovarian weights were reduced in the female Immp2l-/- mice, ovarian follicle growth and development were stunted in the secondary follicle stage. Although a few ovarian follicles were ovulated, the oocytes were not fertilized because of mitochondrial dysfunction. Increased oxidative stress, decreased estrogen levels, and altered genes expression of Wnt/β-catenin and steroid hormone synthesis pathways were observed in 28-day-old Immp2l-/- mice. The Immp2l mutation accelerated ovarian aging process, as no ovarian follicles were detected by age 5 months in Immp2l-/- mice. All the aforementioned changes in the Immp2l-/- mice were reversed by administration of antioxidant melatonin to the Immp2l-/- mice. Furthermore, our in vitro study using Immp2l knockdown granulosa cells confirmed that the Immp2l downregulation induced granulosa cell aging by enhancing reactive oxygen species (ROS) levels, suppressing Wnt16, increasing β-catenin, and decreasing steroid hormone synthesis gene cyp19a1 and estrogen levels, accompanied by an increase in the aging phenotype of granulosa cells. Melatonin treatment delayed granulosa cell aging progression. Taken together, Immp2l causes ovarian aging through the ROS-Wnt/β-catenin-estrogen (cyp19a1) pathway, which can be reversed by melatonin treatment.

Insights

Mitochondrial gene Immp2l deficiency causes infertility and ovarian aging in mice by increasing oxidative stress and altering key pathways. Antioxidant melatonin treatment reversed these effects, highlighting a potential therapeutic strategy.

Area of Science:

Reproductive biology
Mitochondrial genetics
Cellular aging

Background:

Mitochondria are crucial for ovarian follicle development.
Mitochondrial dysfunction, including gene deficiencies, negatively impacts ovarian function.
The role of the mitochondrial inner membrane gene Immp2l in ovarian development is largely unexplored.

Purpose of the Study:

To investigate the function and mechanism of Immp2l in ovarian follicle growth and development.
To determine the impact of Immp2l deficiency on fertility and ovarian aging.
To explore the potential of melatonin as a therapeutic intervention.

Main Methods:

Generation and analysis of Immp2l knockout (Immp2l-/-) and heterozygous (Immp2l+/-) mice.
Assessment of ovarian weight, follicle development, oocyte fertilization, oxidative stress, hormone levels, and gene expression.
In vitro studies using Immp2l knockdown granulosa cells.
Administration of antioxidant melatonin to Immp2l-/- mice.

Main Results:

Female Immp2l-/- mice exhibited infertility, reduced ovarian weight, and stunted follicle development.
Mitochondrial dysfunction, increased oxidative stress, decreased estrogen, and altered Wnt/β-catenin and steroidogenesis pathways were observed in Immp2l-/- mice.
Immp2l deficiency accelerated ovarian aging, with no follicles detected by 5 months.
Melatonin treatment reversed infertility and aging phenotypes in Immp2l-/- mice.
In vitro, Immp2l knockdown in granulosa cells induced aging phenotypes, which were mitigated by melatonin.

Conclusions:

Immp2l is essential for normal ovarian follicle development and fertility.
Immp2l deficiency leads to premature ovarian aging via the ROS-Wnt/β-catenin-estrogen pathway.
Melatonin effectively reverses the detrimental effects of Immp2l deficiency on ovarian function and aging.

Read full analysis

Keywords:

Immp2l Mutation ROS Wnt/β-catenin estrogen granulosa cells mitochondrion ovarian aging

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