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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\u2010related 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\u2010OE increases ROS levels, decreases mitochondrial membrane potential, ATP content and the mtDNA\/nDNA ratio. Further studies showed that Rab9\u2010OE activates the PINK1\u2010PARKIN 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\u2010related 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\u2010related deterioration of oocyte quality.<\/jats:p>","DOI":"10.1111\/acel.14449","type":"journal-article","created":{"date-parts":[[2024,12,15]],"date-time":"2024-12-15T23:14:31Z","timestamp":1734304471000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Age\u2010associated accumulation of\n                    <scp>RAB9<\/scp>\n                    disrupts oocyte meiosis"],"prefix":"10.1111","volume":"24","author":[{"given":"Min","family":"Gao","sequence":"first","affiliation":[{"name":"Key Laboratory of Reproductive Medicine of Guangdong Province, The First Affiliated Hospital and School of Life Sciences Sun Yat\u2010Sen University  Guangzhou China"},{"name":"MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences Sun Yat\u2010Sen University  Guangzhou China"},{"name":"Key Laboratory of Reproductive Health Diseases Research and Translation of Ministry of Education, The First Affiliated Hospital Hainan Medical University  Haikou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Reproductive Medical Center Guangdong Women and Children Hospital  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tengteng","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Reproductive Medicine of Guangdong Province, The First Affiliated Hospital and School of Life Sciences Sun Yat\u2010Sen University  Guangzhou China"},{"name":"MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences Sun Yat\u2010Sen University  Guangzhou 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