Work

Iron regulatory protein 1-deficient mice exhibit hypospermatogenesis

Year: 2024

Type: article

Abstract: Imbalances in testicular iron levels are linked to compromised sperm production and male infertility. Iron regulatory proteins (IRP) 1 and 2 play crucial roles in cellular iron regulation. We investigated the role of IRP1 on spermatogenesis using Irp 1-deficient mice ( Irp 1 −/− ). Histological analysis of the testis of Irp 1 −/− mice revealed hypospermatogenesis with a significant reduction in the number of elongated spermatids and daily sperm production compared to wild-type (WT) mice. Flow cytometry of germ cells from WT and Irp 1 −/− mice showed reduction in spermatocytes and round and elongated spermatids in Irp 1 −/− mice, which was confirmed by histological and immunofluorescence quantification. Finally, stage VIII of spermatogenesis, crucial for spermatid maturation, was less frequent in Irp 1 −/− testicular cross-sections. Hypospermatogenesis worsened with age despite unchanged intratesticular iron levels. Mechanistically, this was due to increased oxidative stress indicated by elevated 8-Oxoguanine (8-OxoG) levels, a DNA lesion resulting from reactive oxygen species (ROS). Furthermore, bulk RNA-seq data indicated compromised DNA damage repair and cell cycle processes, including mitosis and meiosis in Irp 1 −/− mice, which may explain hypospermatogenesis. Our results suggest that IRP1 deletion leads to hypospermatogenesis due to impaired cell cycle progression, decreased DNA damage repair capacity, and oxidative damage. Altogether, this study uncovers a role for IRP1, independent of traditional mechanisms of iron regulation.

Source: Journal of Biological Chemistry

DOI: 10.1016/j.jbc.2024.108067