Mouse study and clinical serum analysis demonstrating that MOTS-c levels are significantly reduced in men with oligoasthenozoospermia, correlating with semen quality, and that MOTS-c protects spermatogenesis by targeting SLC7A11 to suppress ferroptosis—a form of iron-dependent oxidative cell death. Exogenous MOTS-c treatment restored sperm concentration and seminiferous tubule architecture. Identifies ferroptosis suppression via SLC7A11 as a novel MOTS-c mechanism in male reproductive protection—establishing circulating MOTS-c as both a biomarker of male fertility and a potential therapeutic target for oxidative stress-driven spermatogenic dysfunction.
Abstract
Mitochondrial function is critical for spermatogenesis and male fertility. MOTS-c, a mitochondrially encoded regulatory peptide, has recently been reported to effectively protect testicular spermatogenesis in mice, but its specific role and mechanism remain unclear. This study first demonstrated that MOTS-c levels were significantly reduced in the serum of patients with oligoasthenozoospermia, and these levels correlated with semen quality parameters. Spermatogenic dysfunction, including decreased sperm concentration, disrupted seminiferous tubule architecture, and a reduction in spermatogonia, was induced by mechanical stress through microgravity model. Notably, exogenous MOTS-c ameliorated spermatogenic impairment by suppressing oxidative stress and ferroptosis induced by mechanical stress. Solute Carrier Family 7 Member 11 (SLC7A11), a key molecule in ferroptosis, was identified as a target of MOTS-c. Moreover, loss- and gain-of-function studies showed that SLC7A11 inhibited ferroptosis and oxidative stress and promoted spermatogonia proliferation. Furthermore, MOTS-c enhanced the protection against spermatogenic impairment by increasing SLC7A11 levels under mechanical stress. Collectively, this study elucidates the crucial role of MOTS-c in protecting spermatogenesis by antagonizing ferroptosis, providing a theoretical foundation for its potential therapeutic use in male infertility associated with spermatogenic defects.