Nme8 is essential for protection against chemotherapy drug cisplatin-induced male reproductive toxicity in mice

• Published in: Cell death & disease Vol. 15; no. 10; pp. 730 - 12
• Main Authors: Zhu, Haixia, Wang, Hongxiang, Wang, Dan, Liu, Shuqiao, Sun, Xiaoli, Qu, Zhengjiang, Zhang, Aizhen, Ye, Chao, Li, Runze, Wu, Bin, Liu, Min, Gao, Jiangang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.10.2024; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/1; 14/19; 14/35; 631/80/82/39; 64/60; 692/699/2732/1577; 82/51; 82/80; Animals; Antibodies; Antineoplastic Agents - adverse effects; Antineoplastic Agents - toxicity; Autophagy; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Chemotherapy; Cisplatin; Cisplatin - adverse effects; Cisplatin - toxicity; DNA Damage; Exons; Fertility; Humans; Immunology; Life Sciences; Lipid peroxidation; Male; Meiosis; Mice; Mice, Inbred C57BL; NM23 Nucleoside Diphosphate Kinases - genetics; NM23 Nucleoside Diphosphate Kinases - metabolism; Reactive Oxygen Species - metabolism; Sperm; Sperm Motility - drug effects; Spermatogenesis; Spermatogenesis - drug effects; Spermatogonia; Spermatozoa - drug effects; Spermatozoa - metabolism; Testes; Testis - drug effects; Testis - metabolism; Testis - pathology; Thioredoxin; Toxicity
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-024-07118-2

Cisplatin (CP), a chemotherapy drug commonly used in cancers treatment, causes serious reproductive toxicity. With younger cancer patients and increasing survival rates, it is important to preserve their reproductive capacity. NME8 is highly expressed in testis and contains thioredoxin and NDPK domains, suggesting it may be a target against the CP-induced reproductive toxicity. We deleted exons 6–7 of the Nme8 in mice based on human mutation sites and observed impaired transcript splicing. In mice, Nme8 was not essential for spermatogenesis, possibly due to functional compensation by its paralog, Nme5 . Nme8 expression was elevated and translocated to the nucleus in response to two weeks of CP treatment. Under CP treatment, Nme8 deficiency further impaired antioxidant capacity, induced lipid peroxidation and increased ROS level, and failed to activate autophagy, resulting in aggravated DNA damage in testes and sperm. Consequently, the proliferation and differentiation of spermatogonia and the meiosis of spermatocyte were almost completely halted, and sperm motility was impaired. Our research indicates that NME8 protects against CP-induced testis and sperm damage. This may provide new insights into the physiological functions of the Nme family and potential targets for preserving fertility in young male cancer patients.