DOI: 10.5061/dryad.hmgqnk9db
title: The Immp2l mutation causes ovarian aging through ROS-wnt/β-catenin-estrogen (cyp19a1) pathway: preventive effect of melatonin

description: Mitochondria play important roles in ovarian follicle development.
 Mitochondrial dysfunction, including mitochondrial gene deficiency,
 impairs the ovarian development. Here, we explored the role and mechanism
 of mitochondrial inner membrane gene Immp2l in ovarian follicle growth and
 development. Our results revealed that the female Immp2l-/- mice were
 infertile, while the Immp2l+/- mice were normal. Body and ovarian weights
 were reduced in the female Immp2l-/- mice, ovarian follicle growth and
 development were stunted in the secondary follicle stage. Although a few
 ovarian follicles were ovulated, the oocytes were not fertilized due to
 mitochondrial dysfunction. Increased oxidative stress, decreased estrogen
 levels, and altered genes expression of Wnt/β-catenin and steroid hormone
 synthesis pathways were observed in 28-day-old Immp2l-/- mice. The Immp2l
 mutation accelerated ovarian aging process, as no ovarian follicles were
 detected in age of 5 months in Immp2l-/- mice. All the aforementioned
 changes in the Immp2l-/- mice were reversed by administration of
 antioxidant melatonin to the Immp2l-/- mice. Furthermore, our in vitro
 study using Immp2l knockdown granulosa cells confirmed that the Immp2l
 downregulation induced granulosa cell aging by enhancing ROS levels,
 suppressing Wnt16, increasing β-catenin and decreasing steroid hormone
 synthesis gene cyp19a1 and estrogen levels, accompanied by an increase in
 the aging phenotype of granulosa cells. Melatonin treatment delayed
 granulosa cell aging progression. Taken together, Immp2l causes ovarian
 aging through the ROS-Wnt/β-catenin-estrogen (cyp19a1) pathway, which can
 be reversed by melatonin treatment.Mitochondria play important roles in
 ovarian follicle development. Mitochondrial dysfunction, including
 mitochondrial gene deficiency, impairs the ovarian development. Here, we
 explored the role and mechanism of mitochondrial inner membrane gene
 Immp2l in ovarian follicle growth and development. Our results revealed
 that the female Immp2l-/- mice were infertile, while the Immp2l+/- mice
 were normal. Body and ovarian weights were reduced in the female Immp2l-/-
 mice, ovarian follicle growth and development were stunted in the
 secondary follicle stage. Although a few ovarian follicles were ovulated,
 the oocytes were not fertilized due to mitochondrial dysfunction.
 Increased oxidative stress, decreased estrogen levels, and altered genes
 expression of Wnt/β-catenin and steroid hormone synthesis pathways were
 observed in 28-day-old Immp2l-/- mice. The Immp2l mutation accelerated
 ovarian aging process, as no ovarian follicles were detected in age of 5
 months in Immp2l-/- mice. All the aforementioned changes in the Immp2l-/-
 mice were reversed by administration of antioxidant melatonin to the
 Immp2l-/- mice. Furthermore, our in vitro study using Immp2l knockdown
 granulosa cells confirmed that the Immp2l downregulation induced granulosa
 cell aging by enhancing ROS levels, suppressing Wnt16, increasing
 β-catenin and decreasing steroid hormone synthesis gene cyp19a1 and
 estrogen levels, accompanied by an increase in the aging phenotype of
 granulosa cells. Melatonin treatment delayed granulosa cell aging
 progression. Taken together, Immp2l causes ovarian aging through the
 ROS-Wnt/β-catenin-estrogen (cyp19a1) pathway, which can be reversed by
 melatonin treatment.