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Interactions of glutathione, reactive oxygen species, and lipids on oocyte mitochondrial function

谷胱甘肽、活性氧和脂质对卵母细胞线粒体功能的相互作用

基本信息

批准号：
10004697
负责人：
Ulrike Luderer
金额：
$ 18.62万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10004697
关键词：
Address Adipose tissue Affect Age Aging Antioxidants Biogenesis Birth Body Weight Cells Characteristics Chronic Complement DNA Damage DNA copy number Data Development Diet Embryo Enzymes Fatty Acids Female Follicular Fluid Functional disorder GCLC gene GCLM gene Gene Expression Generations Genes Genetic Polymorphism Glutamate-Cysteine Ligase Glutathione Hepatic High Fat Diet Homeostasis Human In Vitro Intervention Knockout Mice Knowledge Link Lipids Liver Mitochondria Measures Membrane Potentials Metaphase Mitochondria Mitochondrial DNA Modeling Mus NADH Oocytes Ovarian Ovarian Follicle Ovarian aging Oxidation-Reduction Oxidative Stress Oxygen Consumption Palmitates Pathologic Pathway interactions Premature Ovarian Failure Primordial Follicle Production Proteins Puberty Publishing Reactive Oxygen Species Research Resistance Serum Source Sulfhydryl Compounds Testing Triglycerides Weight Woman age related assisted reproduction blastocyst blood lipid diminished ovarian reserve emerging adult experience improved in vivo innovation lipid biosynthesis lipid metabolism macromolecule mitochondrial dysfunction mitochondrial membrane mortality mouse model oocyte quality ovarian reserve oxidation oxidative damage oxidized lipid preimplantation reproductive senescence transcriptomics young adult zygote

项目摘要

PROJECT SUMMARY/ABSTRACT Mature oocytes have among the highest intracellular concentrations of the potent antioxidant glutathione (GSH). Female mice lacking the modifier subunit of glutamate cysteine ligase (GCLM), the rate-limiting enzyme in GSH synthesis, have low GSH concentrations in oocytes, poor oocyte quality that manifests as increased embryonic mortality prior to the blastocyst stage, chronic ovarian oxidative stress, and accelerated post-pubertal, age-related decline in the primordial follicle pool, which constitutes the irreplaceable ovarian reserve. Therefore, compared to many genetically modified mouse models, which have complete ovarian follicle depletion prior to puberty, these mice more closely model pathological conditions with diminished ovarian reserve in humans. Female Gclm null mice are also resistant to diet- and age-associated gains in body weight and adipose tissue, have decreased hepatic expression of lipogenesis genes, and have increased hepatic mitochondrial oxygen consumption; however, the effects of Gclm deletion on oocyte lipid metabolism and mitochondrial function have not been studied. Gclm null mice thus constitute an excellent model in which to investigate the hypothesis that GSH deficiency causes oocyte mitochondrial dysfunction via increased reactive oxygen species that directly damage mitochondrial macromolecules and/or via decreased lipogenesis resulting in decreased oocyte mitochondrial fatty acid beta oxidation. This hypothesis will be tested via two specific aims: 1) Determine whether oocyte GSH deficiency due to Gclm deletion results in increased oocyte mitochondrial ROS generation, mitochondrial oxidative lipid and DNA damage, and decreased mitochondrial function. 2) Assess the effects of Gclm deficiency on the serum and oocyte lipidomes and on lipogenesis and fatty acid beta oxidation in the oocyte. The proposed studies will address the knowledge gap in understanding the association between decreased ovarian reserve and poor oocyte quality by examining whether oxidative damage to oocyte mitochondria and disruption of oocyte lipid homeostasis are mechanistically involved in decreased oocyte quality in Gclm-/- mice.

项目概要/摘要成熟卵母细胞具有最高的细胞内浓度的有效抗氧化剂谷胱甘肽（还原型谷胱甘肽）。缺乏谷氨酸半胱氨酸连接酶（GCLM）修饰亚基的雌性小鼠，该修饰亚基是限速因子谷胱甘肽合成酶，卵母细胞中谷胱甘肽浓度低，卵母细胞质量差，表现为囊胚阶段之前的胚胎死亡率增加、慢性卵巢氧化应激和加速青春期后，与年龄相关的原始卵泡池（构成不可替代的卵巢）的衰退预订。因此，与许多具有完整卵巢的转基因小鼠模型相比由于青春期前的卵泡耗竭，这些小鼠更接近地模拟了病理状况，并且减少了人类的卵巢储备。雌性 Gclm 缺失小鼠也能抵抗饮食和年龄相关的身体增长体重和脂肪组织，脂肪生成基因的肝脏表达减少，并增加肝线粒体耗氧量；然而，Gclm缺失对卵母细胞脂质代谢的影响和线粒体功能尚未研究。 Gclm 无效小鼠因此构成了一个优秀的模型，其中调查 GSH 缺乏通过增加卵母细胞线粒体功能障碍而导致卵母细胞线粒体功能障碍的假设活性氧直接损害线粒体大分子和/或通过减少脂肪生成导致卵母细胞线粒体脂肪酸β氧化减少。该假设将通过两个方面进行检验具体目标： 1) 确定 Gclm 缺失导致的卵母细胞 GSH 缺乏是否会导致卵母细胞增加线粒体 ROS 生成、线粒体氧化脂质和 DNA 损伤以及线粒体减少功能。 2) 评估 Gclm 缺乏对血清和卵母细胞脂质组以及脂肪生成和卵母细胞中的脂肪酸β氧化。拟议的研究将解决理解方面的知识差距通过检查氧化是否会降低卵巢储备功能下降与卵母细胞质量差之间的关联卵母细胞线粒体的损伤和卵母细胞脂质稳态的破坏在机制上涉及 Gclm-/- 小鼠卵母细胞质量下降。