Stress granule clearance mediated by V-ATPase-interacting protein NCOA7 mitigates ovarian aging

Area of Science:

• Reproductive biology
• Cellular senescence
• Aging research

Background:

• Reproductive longevity is crucial for female fertility and healthy aging.
• The role of stress response, particularly stress granule accumulation, in ovarian aging is not well understood.
• Effective interventions for ovarian aging are currently lacking.

Purpose of the Study:

• To investigate the role of Nuclear Receptor Coactivator 7 (NCOA7) in ovarian aging.
• To elucidate the mechanism by which NCOA7 influences stress granule dynamics and cellular senescence in the ovary.
• To identify potential therapeutic targets for alleviating ovarian aging.

Main Methods:

• Identified mutations and decreased expression of NCOA7 in women with ovarian aging.
• Utilized NCOA7 deletion mouse models to study its effect on ovarian aging and fertility.
• Investigated the molecular mechanism of NCOA7 in stress granule formation and degradation.
• Employed rapamycin and NCOA7 mRNA delivery to modulate granulophagy and assess its impact on cellular senescence and ovarian aging in vitro and in vivo.

Main Results:

• Deleterious mutations and reduced NCOA7 expression were observed in women experiencing ovarian aging.
• NCOA7 deletion accelerated oxidative stress-induced cellular senescence, ovarian aging, and reduced fecundity in mice.
• NCOA7 facilitates autophagic degradation of stress granules by interacting with G3BP1-V-ATPase.
• Enhancing granulophagy via rapamycin or NCOA7 mRNA delivery accelerated stress granule clearance, alleviated granulosa cell senescence, and delayed ovarian aging in mice.

Conclusions:

• NCOA7 plays a critical role in maintaining ovarian resilience to stress by regulating stress granule clearance.
• The NCOA7-mediated pathway for stress granule degradation represents a novel mechanism influencing ovarian aging.
• Targeting granulophagy or restoring NCOA7 function offers potential therapeutic strategies to mitigate ovarian aging and support female reproductive health.