Age-associated accumulation of RAB9 disrupts oocyte meiosis

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.