Environmental Health Sciences Graduate Program, University of California, Irvine, CA, USA.
Department of Environmental and Occupational Health, University of California, Irvine, CA, USA.
Biol Reprod. 2022 Jun 13;106(6):1218-1231. doi: 10.1093/biolre/ioac032.
Glutathione (GSH) is a tripeptide thiol antioxidant that has been shown to be important to overall reproductive health. Glutamate cysteine ligase, the rate-limiting enzyme in GSH synthesis consists of a catalytic and a modifier (GCLM) subunit. We previously showed that oxidative stress in the ovary and oocytes of Gclm-/- mice is associated with accelerated age-related decline in ovarian follicles and decreased female fertility due to preimplantation embryonic mortality. Mammalian preimplantation development is a highly regulated and energy-intensive process that primarily relies on coordination between lipid droplets (LDs) and mitochondria to maintain cellular homeostasis. In this study, we hypothesized that GSH deficiency in oocytes increases oxidative stress, leading to increased mitochondrial dysfunction and decreased LD consumption, thereby decreasing oocyte developmental competence. We observed that Gclm-/- oocytes have increased oxidative stress, primarily in the form of mitochondrial superoxide and decreased subcortical mitochondrial clusters. Further, Gclm-/- oocytes have decreased mitochondrial membrane potential (ΔΨm) compared with Gclm+/+. We surmise this is likely due to the decreased availability of LDs, as we observed a significant decrease in LD content in Gclm-/- oocytes compared with Gclm+/+. The decreased oocyte LD content is likely related to an altered serum lipidome, with Gclm-/- serum having relatively lower unsaturated fatty acids and triglycerides than that of Gclm+/+ and Gclm+/- females. Altogether these data support that decreased LDs and increased oxidative stress are primary drivers of decreased oocyte developmental competence in GSH-deficient oocytes.
谷胱甘肽（GSH）是一种三肽硫醇抗氧化剂，对整体生殖健康非常重要。谷胱甘肽合成的限速酶谷氨酸半胱氨酸连接酶由一个催化亚基和一个调节亚基（GCLM）组成。我们之前的研究表明，Gclm-/- 小鼠卵巢和卵母细胞中的氧化应激与卵巢卵泡的加速衰老以及由于着床前胚胎死亡导致的雌性生育力下降有关。哺乳动物的着床前发育是一个高度受调控和能量密集的过程，主要依赖于脂滴（LDs）和线粒体之间的协调来维持细胞内稳态。在这项研究中，我们假设卵母细胞中的 GSH 缺乏会增加氧化应激，导致线粒体功能障碍增加和 LD 消耗减少，从而降低卵母细胞的发育能力。我们观察到 Gclm-/-卵母细胞的氧化应激增加，主要表现为线粒体超氧阴离子增加和皮质下线粒体簇减少。此外，Gclm-/-卵母细胞的线粒体膜电位（ΔΨm）与 Gclm+/+相比降低。我们推测这可能是由于 LD 的可用性降低所致，因为我们观察到 Gclm-/-卵母细胞中的 LD 含量与 Gclm+/+相比显著减少。卵母细胞 LD 含量的减少可能与血清脂质组的改变有关，Gclm-/-血清中的不饱和脂肪酸和甘油三酯相对低于 Gclm+/+和 Gclm+/-雌性。总之，这些数据表明，LD 减少和氧化应激增加是 GSH 缺乏卵母细胞中卵母细胞发育能力下降的主要驱动因素。
