Age-associated accumulation of RAB9 disrupts oocyte meiosis.

IF 8 1区 医学 Q1 CELL BIOLOGY Aging Cell Pub Date : 2024-12-15 DOI:10.1111/acel.14449
Min Gao, Fang Wang, Tengteng Xu, Yanling Qiu, Tianqi Cao, Simiao Liu, Wenlian Wu, Yitong Zhou, Haiying Liu, Fenghua Liu, Junjiu Huang
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Abstract

The critical role of some RAB family members in oocyte meiosis has been extensively studied, but their role in oocyte aging remains poorly understood. Here, we report that the vesicle trafficking regulator, RAB9 GTPase, is essential for oocyte meiosis and aging in humans and mice. RAB9 was mainly located at the meiotic spindle periphery and cortex during oocyte meiosis. In humans and mice, we found that the RAB9 protein level were significantly increased in old oocytes. Age-related accumulation of RAB9 inhibits first polar body extrusion and reduces the developmental potential of oocytes. Further studies showed that increased Rab9 disrupts spindle formation and chromosome alignment. In addition, Rab9 overexpression disrupts the actin cap formation and reduces the cortical actin levels. Mechanically, Rab9-OE increases ROS levels, decreases mitochondrial membrane potential, ATP content and the mtDNA/nDNA ratio. Further studies showed that Rab9-OE activates the PINK1-PARKIN mitophagy pathway. Importantly, we found that reducing RAB9 protein expression in old oocytes could partially improve the rate of old oocyte maturation, ameliorate the accumulation of age-related ROS levels and spindle abnormalities, and partially rescue ATP levels, mtDNA/nDNA ratio, and PINK1 and PARKIN expression. In conclusion, our results suggest that RAB9 is required to maintain the balance between mitochondrial function and meiosis, and that reducing RAB9 expression is a potential strategy to ameliorate age-related deterioration of oocyte quality.

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一些 RAB 家族成员在卵母细胞减数分裂中的关键作用已被广泛研究,但它们在卵母细胞衰老中的作用仍鲜为人知。在此,我们报告了囊泡贩运调节因子 RAB9 GTPase 对人类和小鼠卵母细胞减数分裂和衰老的重要作用。在卵母细胞减数分裂过程中,RAB9 主要位于减数纺锤体外围和皮层。在人类和小鼠中,我们发现老年卵母细胞中的 RAB9 蛋白水平显著升高。与年龄相关的 RAB9 累积抑制了第一极体的挤出,降低了卵母细胞的发育潜能。进一步的研究表明,Rab9的增加会破坏纺锤体的形成和染色体的排列。此外,Rab9 过表达会破坏肌动蛋白帽的形成,降低皮质肌动蛋白水平。从机理上讲,Rab9-OE 增加了 ROS 水平,降低了线粒体膜电位、ATP 含量和 mtDNA/nDNA 比率。进一步的研究表明,Rab9-OE 激活了 PINK1-PARKIN 的有丝分裂途径。重要的是,我们发现减少老卵母细胞中 RAB9 蛋白的表达可部分提高老卵母细胞的成熟速度,改善与年龄相关的 ROS 水平积累和纺锤体异常,并部分挽救 ATP 水平、mtDNA/nDNA 比率以及 PINK1 和 PARKIN 的表达。总之,我们的研究结果表明,RAB9 是维持线粒体功能和减数分裂之间平衡的必要条件,减少 RAB9 的表达是改善与年龄相关的卵母细胞质量恶化的一种潜在策略。
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来源期刊
Aging Cell
Aging Cell Biochemistry, Genetics and Molecular Biology-Cell Biology
自引率
2.60%
发文量
212
期刊介绍: Aging Cell is an Open Access journal that focuses on the core aspects of the biology of aging, encompassing the entire spectrum of geroscience. The journal's content is dedicated to publishing research that uncovers the mechanisms behind the aging process and explores the connections between aging and various age-related diseases. This journal aims to provide a comprehensive understanding of the biological underpinnings of aging and its implications for human health. The journal is widely recognized and its content is abstracted and indexed by numerous databases and services, which facilitates its accessibility and impact in the scientific community. These include: Academic Search (EBSCO Publishing) Academic Search Alumni Edition (EBSCO Publishing) Academic Search Premier (EBSCO Publishing) Biological Science Database (ProQuest) CAS: Chemical Abstracts Service (ACS) Embase (Elsevier) InfoTrac (GALE Cengage) Ingenta Select ISI Alerting Services Journal Citation Reports/Science Edition (Clarivate Analytics) MEDLINE/PubMed (NLM) Natural Science Collection (ProQuest) PubMed Dietary Supplement Subset (NLM) Science Citation Index Expanded (Clarivate Analytics) SciTech Premium Collection (ProQuest) Web of Science (Clarivate Analytics) Being indexed in these databases ensures that the research published in Aging Cell is discoverable by researchers, clinicians, and other professionals interested in the field of aging and its associated health issues. This broad coverage helps to disseminate the journal's findings and contributes to the advancement of knowledge in geroscience.
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