The Critical Role of Enhanced OXPHOS and Mitochondrial Hyperpolarization in Simulated Microgravity‐Induced Oocyte Maturation Arrest

Abstract Meiosis is essential for sexual reproduction, yet the impact of microgravity on oocyte maturation remains unclear, raising concerns for reproductive success in space environments. Here, it is examined the effects of simulated microgravity (SMG) on mouse oocytes and found that SMG impaired mitochondrial function, evidenced by elevated oxidative phosphorylation and mitochondrial membrane hyperpolarization, resulting in meiotic arrest. This response is distinct from that induced by other stressors or seen in somatic cells under microgravity, highlighting the unique sensitivity of oocytes. SMG also caused mitochondrial mislocalization, which activated the unfolded protein response and suppressed mitochondrial gene expression. Despite accelerating meiotic progression, SMG delayed microtubule‐organizing center (MTOC) coalescence. This misalignment led to spindle defects, reduced polar body extrusion, and increased aneuploidy, compromising oocyte quality. The spindle assembly checkpoint (SAC) remained functional, suggesting mitochondrial dysregulation‐not SAC failure‐drives meiotic acceleration. Notably, even oocytes that reached maturation under SMG exhibited polarity loss and reduced developmental potential. Extending metaphase I by inhibiting the anaphase‐promoting complex rescued MTOC assembly and spindle formation, significantly improving maturation rates. These findings identify mitochondrial dysfunction as a key mediator of SMG‐induced meiotic failure and propose M‐phase regulation as a strategy to safeguard female fertility in space environments.