Species: mouse
Mutation name:
type: null mutation
fertility: infertile - ovarian defect
Comment: A mutation in the inner mitochondrial membrane peptidase 2-like gene (Immp2l) affects mitochondrial function and impairs fertility in mice. Lu B et al. (2008) The mitochondrion is involved in energy generation, apoptosis regulation, and calcium homeostasis. Mutations in genes involved in mitochondrial processes often result in a severe phenotype or embryonic lethality, making the study of mitochondrial involvement in aging, neurodegeneration, or reproduction challenging. Using a transgenic insertional mutagenesis strategy, we generated a mouse mutant, Immp2lTg(Tyr)979Ove, with a mutation in the inner mitochondrial membrane peptidase 2-like (Immp2l) gene. The mutation affected the signal peptide sequence processing of mitochondrial proteins cytochrome c1 and glycerol phosphate dehydrogenase 2. The inefficient processing of mitochondrial membrane proteins perturbed mitochondrial function so that mitochondria from mutant mice manifested hyperpolarization, higher than normal superoxide ion generation, and higher levels of ATP. Homozygous Immp2lTg(Tyr)979Ove females were infertile due to defects in folliculogenesis and ovulation, whereas mutant males were severely subfertile due to erectile dysfunction. The data suggest that the high superoxide ion levels lead to a decrease in the bioavailability of nitric oxide and an increase in reactive oxygen species stress, which underlies these reproductive defects. The results provide a novel link between mitochondrial dysfunction and infertility and suggest that superoxide ion targeting agents may prove useful for treating infertility in a subpopulation of infertile patients.//////////////////

Species: mouse
Mutation name:
type: null mutation
fertility: infertile - ovarian defect
Comment: The Immp2l mutation causes ovarian aging through ROS-Wnt/β-catenin-estrogen pathway: preventive effect of melatonin. He Q et al. (2020) 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.//////////////////