卵母细胞通过选择性失活小鼠体内的胆固醇生物合成来协调线粒体功能的蛋白质异戊二烯化。

The Journal of Biological Chemistry Pub Date : 2023-10-01 Epub Date: 2023-08-21 DOI:10.1016/j.jbc.2023.105183
Yongjuan Sang, Qiwen Yang, Yueshuai Guo, Xiaofei Liu, Di Shen, Chen Jiang, Xinying Wang, Kang Li, Haiquan Wang, Chaofan Yang, Lijun Ding, Haixiang Sun, Xuejiang Guo, Chaojun Li
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摘要

新出现的研究和临床证据表明,卵母细胞的代谢活性可能在生殖异常中发挥关键作用。然而,代谢酶调控卵母细胞发育的内在机制在很大程度上仍然未知。我们的研究表明,香叶基香叶基二磷酸合成酶1(Ggps1)是甲羟戊酸途径中负责从法尼基焦磷酸合成类异戊二烯代谢产物香叶基香叶基焦磷酸的关键酶,对小鼠卵母细胞成熟至关重要。我们的研究结果表明,在完全发育的卵母细胞中,阻止蛋白质异戊二烯化的Ggps1缺失会导致生育能力低下和后代代谢缺陷,而不会影响卵泡发育。缺乏Ggps1的卵母细胞表现出线粒体稳态紊乱,卵母细胞产生的线粒体缺陷由胎儿后代遗传。从机制上讲,线粒体核糖体蛋白Dap3的过度法尼酰化和小G蛋白水平的降低介导了Ggps1缺乏诱导的线粒体功能障碍。此外,当雌性暴露于高胆固醇饮食时,卵母细胞中Ggps1水平的显著降低伴随着后代缺陷。总之,这项研究确定了甲羟戊酸途径蛋白异戊二烯化对卵母细胞成熟中的线粒体功能至关重要,并提供了证据表明,法尼焦磷酸和香叶基香叶基焦磷酸之间的失衡导致的蛋白异戊二烯化破坏是高胆固醇诱导的卵母细胞质量受损的主要机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Oocytes orchestrate protein prenylation for mitochondrial function through selective inactivation of cholesterol biosynthesis in murine species.

Emerging research and clinical evidence suggest that the metabolic activity of oocytes may play a pivotal role in reproductive anomalies. However, the intrinsic mechanisms governing oocyte development regulated by metabolic enzymes remain largely unknown. Our investigation demonstrates that geranylgeranyl diphosphate synthase1 (Ggps1), the crucial enzyme in the mevalonate pathway responsible for synthesizing isoprenoid metabolite geranylgeranyl pyrophosphate from farnesyl pyrophosphate, is essential for oocyte maturation in mice. Our findings reveal that the deletion of Ggps1 that prevents protein prenylation in fully grown oocytes leads to subfertility and offspring metabolic defects without affecting follicle development. Oocytes that lack Ggps1 exhibit disrupted mitochondrial homeostasis and the mitochondrial defects arising from oocytes are inherited by the fetal offspring. Mechanistically, the excessive farnesylation of mitochondrial ribosome protein, Dap3, and decreased levels of small G proteins mediate the mitochondrial dysfunction induced by Ggps1 deficiency. Additionally, a significant reduction in Ggps1 levels in oocytes is accompanied by offspring defects when females are exposed to a high-cholesterol diet. Collectively, this study establishes that mevalonate pathway-protein prenylation is vital for mitochondrial function in oocyte maturation and provides evidence that the disrupted protein prenylation resulting from an imbalance between farnesyl pyrophosphate and geranylgeranyl pyrophosphate is the major mechanism underlying impairment of oocyte quality induced by high cholesterol.

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