Kinesin KIF14 insufficiency impairs oocyte quality via cytoskeleton and mitochondria dysfunction during reproductive aging

Age-related deterioration of oocyte quality is a major cause of female infertility. Aged oocytes exhibit meiotic abnormalities and aneuploidy, yet the molecular mechanisms underlying these defects remain poorly defined. Here, we report that KIF14, a member of kinesin-3 family, is indispensable for meiosis in mouse and porcine oocytes, and KIF14 insufficiency drives maturation defects in oocytes during reproductive aging. We found that KIF14 expression is markedly downregulated in aged oocytes, and KIF14 depletion results in aberrant chromosome alignment and subsequent aneuploidy. This abnormality may be attributed to diminished polar ejection force and impaired spindle tension, which arise from altered tubulin acetylation levels modulated by HDAC6. Moreover, KIF14 deficiency reduces actin abundance by regulating multiple actin nucleation factors, thereby disrupting meiotic spindle migration and compromising FIS1-governed mitochondrial function. Additionally, loss of KIF14 induces abnormal mitochondrial distribution and perturbs microtubule-dependent RPS3 transport, which impairs the stability and translational efficiency of stored oocyte mRNAs. Importantly, exogenous supplementation of KIF14 in oocytes from aged mice effectively rescues aging-related deficiencies in polar body extrusion, chromosome alignment, spindle migration, mitochondrial function, and mRNA metabolism. In summary, our findings demonstrate that reduced KIF14 expression is a key contributor to maternal age-associated meiotic defects in mouse oocytes.