Mitochondrial Dynamics Modulate Human Granulosa Cell Steroidogenesis and Female Fertility

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Title:	Mitochondrial Dynamics Modulate Human Granulosa Cell Steroidogenesis and Female Fertility
Authors:	URS, DILIP BHARGAVA SREERANGARAJA
Contributors:	醫學生物科技博士學位學程高淑慧
Keywords:	mitochondria
Date:	2023-06-14
Issue Date:	2023-12-11 13:49:04 (UTC+8)
Abstract:	The successful pregnancy outcome is associated with steroidogenesis in the ovarian follicle that is linked to embryo quality. The follicles contain an oocyte and granulosa cells that produce various hormones, including steroids and peptides. The follicular fluids of women who got impregnated through in vitro fertilization (IVF) contained higher amounts of estradiol compared to those who underwent assisted reproductive technology (ART) but did not conceive, indicating a correlation between estradiol levels and successful fertilization. Ovarian estradiol is biosynthesized in the granulosa cells. The rate-limiting step in early steroidogenesis is the flow of cholesterol from the outer to the inner mitochondrial membrane. In the present study, we hypothesized that the mitochondria in granulosa cells are critical for maintaining oocyte quality and fertility capacity. The study involved obtaining serum, follicular fluids, and granulosa cells from individuals undergoing IVF treatment and recording oocyte numbers, quality, fertilization rate, and pregnancy rate. Patients were categorized into different groups based on their infertility type to investigate the correlation between mitochondrial function and steroid hormone production in granulosa cells, as well as to assess the impact of hormonal levels on fertility potential. Steroid hormone levels, mitochondrial mass and membrane potential, ATP content, and steroidogenic enzyme levels were measured. The study showed that patients with endometriosis had lower estradiol levels and decreased IVF outcomes, and those with ovarian endometrioma had reduced mitochondrial mass and membrane potential, lower enzyme levels, and increased cumulus cell apoptosis. Therefore, we aimed to investigate whether the unbalanced mitochondrial dynamics-mediated mitochondrial dysfunction negatively impacts on steroidogenesis and reproductive outcome. Here, the human granulosa cells (KGN cells) were transfected with three mitochondrial dynamin-related protein (DRP1) variants, wild type (WT), K38A, and S637A DRP1, respectively. Then, the granulosa cells were primed with follicular stimulating hormone and cholesterol. The granulosa cell harboring DRP1 variants showed differential changes in mitochondrial morphology, membrane potential, and ATP levels. Overexpression of DRP1 WT significantly decreased steroidogenic enzyme levels and cytochrome P450 expression, while FSH treatment increased the expression of steroidogenic acute regulatory protein. Overall, we concluded that unbalanced mitochondrial dynamics in human granulosa cells can negatively impact steroidogenesis, fertilization rate, oocyte maturation, and ultimately fertility.
Description:	博士指導教授:高淑慧委員:李慶國委員:張壯榮委員:周雅菁委員:李麗花委員:高淑慧
Data Type:	thesis
Appears in Collections:	[Ph.D. Program in Medical Biotechnology] Dissertations/Theses

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