aMitochondrial-Derived Peptide MOTS-c Targets SLC7A11 to Preserve Spermatogenesis by Suppressing Ferroptosis.

“aMitochondrial-Derived Peptide MOTS-c Targets SLC7A11 to Preserve Spermatogenesis by Suppressing Ferroptosis. Liu S(1), Ru K(2), Shen YJ(2), Yan Y(1), Zhu C(2), Wang H(1), Xu Y(1), Wang X(2), Yang H(2), Zhao S(1), Gong Y(1), Tian Y(3), Qian A(4), Yang H(5), Chen Z(6). Author information: (1)Department of Obstetrics and Gynecology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China. (2)Lab for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering, Key Lab for Space Biosciences and Biotechnology, Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, 710072, China. (3)Lab for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering, Key Lab for Space Biosciences and Biotechnology, Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, 710072, China. Electronic address: tianye@nwpu.edu.cn. (4)Lab for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering, Key Lab for Space Biosciences and Biotechnology, Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, 710072, China. Electronic address: qianair@nwpu.edu.cn. (5)Department of Obstetrics and Gynecology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China. Electronic address: yanghong@fmmu.edu.cn. (6)Lab for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering, Key Lab for Space Biosciences and Biotechnology, Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, 710072, China; Department of Obstetrics and Gynecology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China. Electronic address: chenzhihao@nwpu.edu.cn. 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. Copyright © 2026. Published by Elsevier Inc. Conflict of interest statement: Declaration of Competing Interest The authors declare no competing interests.”