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1.
Hum Reprod ; 2024 Jul 16.
Article in English | MEDLINE | ID: mdl-39013118

ABSTRACT

STUDY QUESTION: Is oocyte developmental competence associated with changes in granulosa cell (GC) metabolism? SUMMARY ANSWER: GC metabolism is regulated by the LH surge, altered by obesity and reproductive aging, and, in women, specific metabolic profiles are associated with failed fertilization versus increased blastocyst development. WHAT IS KNOWN ALREADY: The cellular environment in which an oocyte matures is critical to its future developmental competence. Metabolism is emerging as a potentially important factor; however, relative energy production profiles between GCs and cumulus cells and their use of differential substrates under normal in vivo ovulatory conditions are not well understood. STUDY DESIGN, SIZE, DURATION: This study identified metabolic and substrate utilization profiles within ovarian cells in response to the LH surge, using mouse models and GCs of women undergoing gonadotropin-induced oocyte aspiration followed by IVF/ICSI. PARTICIPANTS/MATERIALS, SETTING, METHODS: To comprehensively assess follicular energy metabolism, we used real-time metabolic analysis (Seahorse XFe96) to map energy metabolism dynamics (mitochondrial respiration, glycolysis, and fatty acid oxidation) in mouse GCs and cumulus-oocyte complexes (COCs) across a detailed time course in the lead up to ovulation. In parallel, the metabolic profile of GCs was measured in a cohort of 85 women undergoing IVF/ICSI (n = 21 with normal ovarian function; n = 64 with ovarian infertility) and correlated with clinical parameters and cycle outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: Our study reveals dynamic changes in GC energy metabolism in response to ovulatory LH, with mitochondrial respiration and glycolysis differentially affected by obesity versus aging, in both mice and women. High respiration in GCs is associated with failed fertilization (P < 0.05) in a subset of women, while glycolytic reserve and mitochondrial ATP production are correlated with on-time development at Day 3 (P < 0.05) and blastocyst formation (P < 0.01) respectively. These data provide new insights into the cellular mechanisms of infertility, by uncovering significant associations between metabolism within the ovarian follicle and oocyte developmental competence. LIMITATIONS, REASONS FOR CAUTION: A larger prospective study is needed before the metabolic markers that were positively and negatively associated with oocyte quality can be used clinically to predict embryo outcomes. WIDER IMPLICATIONS OF THE FINDINGS: This study offers new insights into the importance of GC metabolism for subsequent embryonic development and highlights the potential for therapeutic strategies focused on optimizing mitochondrial metabolism to support embryonic development. STUDY FUNDING/COMPETING INTEREST(S): National Health and Medical Research Council (Australia). The authors have no competing interests. TRIAL REGISTRATION NUMBER: N/A.

2.
Genes (Basel) ; 15(3)2024 03 16.
Article in English | MEDLINE | ID: mdl-38540426

ABSTRACT

Mitochondria undergo a myriad of changes during pre-implantation embryo development, including shifts in activity levels and mitochondrial DNA (mtDNA) replication. However, how these distinct aspects of mitochondrial function are linked and their responsiveness to diverse stressors is not well understood. Here, we show that mtDNA content increased between 8-cell embryos and the blastocyst stage, with similar copy numbers per cell in the inner cell mass (ICM) and trophectoderm (TE). In contrast, mitochondrial membrane potential (MMP) was higher in TE than ICM. Culture in ambient oxygen (20% O2) altered both aspects of mitochondrial function: the mtDNA copy number was upregulated in ICM, while MMP was diminished in TE. Embryos cultured in 20% O2 also exhibited delayed development kinetics, impaired implantation, and reduced mtDNA levels in E18 fetal liver. A model of oocyte mitochondrial stress using rotenone showed only a modest effect on on-time development and did not alter the mtDNA copy number in ICM; however, following embryo transfer, mtDNA was higher in the fetal heart. Lastly, endogenous mitochondrial dysfunction, induced by maternal age and obesity, altered the blastocyst mtDNA copy number, but not within the ICM. These results demonstrate that mitochondrial activity and mtDNA content exhibit cell-specific changes and are differentially responsive to diverse types of oxidative stress during pre-implantation embryogenesis.


Subject(s)
DNA Copy Number Variations , DNA, Mitochondrial , Animals , Mice , DNA, Mitochondrial/genetics , DNA, Mitochondrial/metabolism , DNA Copy Number Variations/genetics , Membrane Potentials , Mitochondria/metabolism , Oxidative Stress/genetics , Embryonic Development/genetics , Oxygen/metabolism
3.
Reproduction ; 164(6): F95-F108, 2022 12 01.
Article in English | MEDLINE | ID: mdl-36111646

ABSTRACT

In brief: Reactive oxygen species are generated throughout the pre-implantation period and are necessary for normal embryo formation. However, at pathological levels, they result in reduced embryo viability which can be mediated through factors delivered by sperm and eggs at conception or from the external environment. Abstract: Reactive oxygen species (ROS) occur naturally in pre-implantation embryos as a by-product of ATP generation through oxidative phosphorylation and enzymes such as NADPH oxidase and xanthine oxidase. Biological concentrations of ROS are required for crucial embryonic events such as pronuclear formation, first cleavage and cell proliferation. However, high concentrations of ROS are detrimental to embryo development, resulting in embryo arrest, increased DNA damage and modification of gene expression leading to aberrant fetal growth and health. In vivo embryos are protected against oxidative stress by oxygen scavengers present in follicular and oviductal fluids, while in vitro, embryos rely on their own antioxidant defence mechanisms to protect against oxidative damage, including superoxide dismutase, catalase, glutathione and glutamylcysteine synthestase. Pre-implantation embryonic ROS originate from eggs, sperm and embryos themselves or from the external environment (i.e. in vitro culture system, obesity and ageing). This review examines the biological and pathological roles of ROS in the pre-implantation embryo, maternal and paternal origins of embryonic ROS, and from a clinical perspective, we comment on the growing interest in combating increased oxidative damage in the pre-implantation embryo through the addition of antioxidants.


Subject(s)
Antioxidants , Xanthine Oxidase , Animals , Male , Reactive Oxygen Species/metabolism , Antioxidants/metabolism , Catalase/metabolism , Xanthine Oxidase/metabolism , Semen/metabolism , Oxidative Stress , Embryonic Development , Embryo, Mammalian/metabolism , Superoxide Dismutase/metabolism , Glutathione/metabolism , Oxygen/metabolism , NADPH Oxidases/metabolism , Adenosine Triphosphate/metabolism , Mammals/metabolism
4.
Reprod Fertil Dev ; 34(13): 855-866, 2022 Aug.
Article in English | MEDLINE | ID: mdl-35836362

ABSTRACT

Against the backdrop of a global pandemic, the Society for Reproductive Biology (SRB) 2021 meeting reunited the Australian and New Zealand reproductive research community for the first time since 2019 and was the first virtual SRB meeting. Despite the recent global research disruptions, the conference revealed significant advancements in reproductive research, the importance of which span human health, agriculture, and conservation. A core theme was novel technologies, including the use of medical microrobots for therapeutic and sperm delivery, diagnostic hyperspectral imaging, and hydrogel condoms with potential beyond contraception. The importance of challenging the contraceptive status quo was further highlighted with innovations in gene therapies, non-hormonal female contraceptives, epigenetic semen analysis, and in applying evolutionary theory to suppress pest population reproduction. How best to support pregnancies, particularly in the context of global trends of increasing maternal age, was also discussed, with several promising therapies for improved outcomes in assisted reproductive technology, pre-eclampsia, and pre-term birth prevention. The unique insights gained via non-model species was another key focus and presented research emphasised the importance of studying diverse systems to understand fundamental aspects of reproductive biology and evolution. Finally, the meeting highlighted how to effectively translate reproductive research into policy and industry practice.


Subject(s)
Contraception , Semen , Australia , Biology , Congresses as Topic , Contraception/methods , Female , Humans , Male , New Zealand , Pregnancy
5.
Sci Adv ; 8(24): eabn4564, 2022 06 17.
Article in English | MEDLINE | ID: mdl-35714185

ABSTRACT

The female ovary contains a finite number of oocytes, and their release at ovulation becomes sporadic and disordered with aging and with obesity, leading to loss of fertility. Understanding the molecular defects underpinning this pathology is essential as age of childbearing and obesity rates increase globally. We identify that fibrosis within the ovarian stromal compartment is an underlying mechanism responsible for impaired oocyte release, which is initiated by mitochondrial dysfunction leading to diminished bioenergetics, oxidative damage, inflammation, and collagen deposition. Furthermore, antifibrosis drugs (pirfenidone and BGP-15) eliminate fibrotic collagen and restore ovulation in reproductively old and obese mice, in association with dampened M2 macrophage polarization and up-regulated MMP13 protease. This is the first evidence that ovarian fibrosis is reversible and indicates that drugs targeting mitochondrial metabolism may be a viable therapeutic strategy for women with metabolic disorders or advancing age to maintain ovarian function and extend fertility.


Subject(s)
Longevity , Ovary , Animals , Collagen/metabolism , Female , Fibrosis , Humans , Mice , Obesity/metabolism , Oocytes/metabolism , Ovary/metabolism , Ovary/pathology
6.
Sci Adv ; 8(24): eabl8070, 2022 06 17.
Article in English | MEDLINE | ID: mdl-35704569

ABSTRACT

Eggs contain about 200,000 mitochondria that generate adenosine triphosphate and metabolites essential for oocyte development. Mitochondria also integrate metabolism and transcription via metabolites that regulate epigenetic modifiers, but there is no direct evidence linking oocyte mitochondrial function to the maternal epigenome and subsequent embryo development. Here, we have disrupted oocyte mitochondrial function via deletion of the mitochondrial fission factor Drp1. Fission-deficient oocytes exhibit a high frequency of failure in peri- and postimplantation development. This is associated with altered mitochondrial function, changes in the oocyte transcriptome and proteome, altered subcortical maternal complex, and a decrease in oocyte DNA methylation and H3K27me3. Transplanting pronuclei of fertilized Drp1 knockout oocytes to normal ooplasm fails to rescue embryonic lethality. We conclude that mitochondrial function plays a role in establishing the maternal epigenome, with serious consequences for embryo development.


Subject(s)
Embryonic Development , Oocytes , Cytoplasm/metabolism , Dynamins/genetics , Dynamins/metabolism , Embryonic Development/genetics , Female , Humans , Mitochondria/metabolism , Oocytes/metabolism , Pregnancy
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