Mitochondrial-derived peptide MOTS-c targets SLC7A11 to preserve spermatogenesis by suppressing ferroptosis.

This study investigated the role of MOTS-c, a mitochondrially encoded regulatory peptide, in protecting spermatogenesis. Researchers first measured serum MOTS-c levels in patients with oligoasthenozoospermia (a condition involving reduced and poorly motile sperm), finding these levels were significantly lower than in fertile controls and correlated positively with semen quality parameters. To model spermatogenic dysfunction mechanistically, the researchers used a microgravity-based mechanical stress model in mice, which induced decreased sperm concentration, disrupted seminiferous tubule architecture, and reduced spermatogonia counts. Exogenous MOTS-c administration was shown to ameliorate these impairments by suppressing oxidative stress and ferroptosis — a form of iron-dependent programmed cell death. The study identified SLC7A11 (Solute Carrier Family 7 Member 11), a known ferroptosis regulator, as a molecular target of MOTS-c. Loss- and gain-of-function experiments confirmed that SLC7A11 inhibits ferroptosis and oxidative stress while promoting spermatogonia proliferation. MOTS-c's protective effects were shown to depend, at least in part, on upregulating SLC7A11 under mechanical stress conditions. Limitations include the small and uncharacterized human cohort, reliance on an indirect mechanical stress model, and predominantly animal/cellular mechanistic data.

Why this grade: The study includes a human observational component (serum MOTS-c levels in oligoasthenozoospermia patients) but the primary mechanistic and interventional findings come from animal and in vitro experiments, limiting direct human evidence strength.