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NAD + precursors promote the restoration of spermatogenesis in busulfan-treated mice through inhibiting Sirt2-regulated ferroptosis.

Authors :
Feng YQ
Liu X
Zuo N
Yu MB
Bian WM
Han BQ
Sun ZY
De Felici M
Shen W
Li L
Source :
Theranostics [Theranostics] 2024 Apr 15; Vol. 14 (6), pp. 2622-2636. Date of Electronic Publication: 2024 Apr 15 (Print Publication: 2024).
Publication Year :
2024

Abstract

Rationale: In recent years, nicotinamide adenine dinucleotide (NAD <superscript>+</superscript> ) precursors (Npre) have been widely employed to ameliorate female reproductive problems in both humans and animal models. However, whether and how Npre plays a role in the male reproductive disorder has not been fully clarified. Methods: In the present study, a busulfan-induced non-obstructive azoospermic mouse model was used, and Npre was administered for five weeks following the drug injection, with the objective of reinstating spermatogenesis and fertility. Initially, we assessed the NAD <superscript>+</superscript> level, germ cell types, semen parameters and sperm fertilization capability. Subsequently, testis tissues were examined through RNA sequencing analysis, ELISA, H&E, immunofluorescence, quantitative real-time PCR, and Western blotting techniques. Results: The results indicated that Npre restored normal level of NAD <superscript>+</superscript> in blood and significantly alleviated the deleterious effects of busulfan (BU) on spermatogenesis, thereby partially reestablishing fertilization capacity. Transcriptome analysis, along with recovery of testicular Fe <superscript>2+</superscript> , GSH, NADPH, and MDA levels, impaired by BU, and the fact that Fer-1, an inhibitor of ferroptosis, restored spermatogenesis and semen parameters close to CTRL values, supported such possibility. Interestingly, the reduction in SIRT2 protein level by the specific inhibitor AGK2 attenuated the beneficial effects of Npre on spermatogenesis and ferroptosis by affecting PGC-1α and ACLY protein levels, thus suggesting how these compounds might confer spermatogenesis protection. Conclusion: Collectively, these findings indicate that NAD <superscript>+</superscript> protects spermatogenesis against ferroptosis, probably through SIRT2 dependent mechanisms. This underscores the considerable potential of Npre supplementation as a feasible strategy for preserving or restoring spermatogenesis in specific conditions of male infertility and as adjuvant therapy to preserve male fertility in cancer patients receiving sterilizing treatments.<br />Competing Interests: Competing Interests: The authors have declared that no competing interest exists.<br /> (© The author(s).)

Details

Language :
English
ISSN :
1838-7640
Volume :
14
Issue :
6
Database :
MEDLINE
Journal :
Theranostics
Publication Type :
Academic Journal
Accession number :
38646657
Full Text :
https://doi.org/10.7150/thno.92416