RAB7 activity is required for the regulation of mitophagy in oocyte meiosis and oocyte quality control during ovarian aging
RAB7 activity is required for the regulation of mitophagy in oocyte meiosis and oocyte quality control during ovarian aging
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DOI：
10.1080/15548627.2021.1946739
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发表时间：
2021-07-08
期刊：
影响因子：
13.3
通讯作者：
Li, Jing
中科院分区：
文献类型：
--
作者：
Jin, Xin;Wang, Kehan;Li, Jing
越来越多的证据表明，线粒体自噬（一种专门用于降解和清除长寿或受损线粒体的自噬形式）在衰老及与年龄相关的疾病中会受损。先前的研究表明，暴露于肥胖环境中的卵母细胞由于无法激活线粒体自噬，从而积累并传递受损的线粒体。然而，线粒体自噬在卵母细胞中是否发挥作用以及卵母细胞衰老中的调控机制是什么，仍不明确。在本研究中，当用解偶联剂羰基氰化物间氯苯腙（CCCP）处理完全成熟的卵母细胞以诱导线粒体自噬时，我们发现PRKN介导的线粒体自噬通路的激活伴随着减数分裂在中期I阶段的阻滞。随后我们的研究结果表明，这与RAB7活性降低有关，并且通过显微注射编码活性RAB7（Q67L）的信使核糖核酸（mRNA）或用RAB7激活剂ML098处理，CCCP处理过的卵母细胞中所有观察到的缺陷都能得到有效挽救。进一步研究表明，PRKN蛋白水平是一个限速因素，它通过泛素 - 蛋白酶体系统促进RAB7及其鸟嘌呤核苷酸交换因子（GEF）复合物CCZ1 - MON1的降解。在卵巢衰老过程中收集的生发泡（GV）期卵母细胞中，我们发现与年龄相关的PINK1和PRKN蛋白增加，而RAB7显著减少，这导致线粒体自噬体形成缺陷和受损线粒体的积累。体内给予ML098处理后，与年龄相关的女性生育能力减退情况得到改善。因此，RAB7活性对于维持线粒体自噬与染色体稳定性之间的平衡是必需的，RAB7激活剂是改善与年龄相关的卵母细胞质量恶化的良好候选物质。
There is increasing evidence that mitophagy, a specialized form of autophagy to degrade and clear long-lived or damaged mitochondria, is impaired in aging and age-related disease. Previous study has demonstrated the obesity-exposed oocytes accumulate and transmit damaged mitochondria due to an inability to activate mitophagy. However, it remains unknown whether mitophagy functions in oocyte and what's the regulatory mechanism in oocyte aging. In the study, when fully grown oocytes were treated with CCCP, an uncoupling agent to induce mitophagy, we found the activation of the PRKN-mediated mitophagy pathway accompanied the blockage of meiosis at metaphase I stage. Our result then demonstrated its association with the decreased activity of RAB7 and all the observed defects in CCCP treated oocytes could be effectively rescued by microinjection of mRNA encoding active RAB7(Q67L) or treatment with the RAB7 activator ML098. Further study indicated PRKN protein level as a rate-limiting factor to facilitate degradation of RAB7 and its GEF (guanine nucleotide exchange factor) complex CCZ1-MON1 through the ubiquitin-proteasome system. In GV oocytes collected during ovarian aging, we found the age-related increase of PINK1 and PRKN proteins and a significant decrease of RAB7 which resulted in defects of mitophagosome formation and the accumulation of damaged mitochondria. The age-related retardation of female fertility was improved after in vivo treatment of ML098. Thus, RAB7 activity is required to maintain the balance between mitophagy and chromosome stability and RAB7 activator is a good candidate to ameliorate age-related deterioration of oocyte quality.