Thioredoxin-1 inhibits granulosa cell ferroptosis to rescue ovarian aging through mitophagy-dependent activation of BNIP3L

Yang, W., Zhang, X., Xu, R., Huang, Z., Ma, Y., Yang, J., Lin, Z., Ma, G., Xu, J., Qiao, Y., Xiao, Z., Cao, J., Li, S., Zhang, X., Hutchins, A., Tong, G.

Southern University of Science and Technology · biorxiv

Paper

Abstract

Ovarian aging is closely associated with a decline in fertility and an increase in reproductive dysfunction. Ovarian granulosa cells (GCs) support oocyte homeostasis and development, yet insight into GC dysfunction during aging is limited. Here, we show that aged GCs of humans and mice have indications of elevated ferroptosis, including increased ferroptosis-related metabolites, lipid peroxidation, and iron accumulation. The ferroptosis inhibitor Ferrostatin-1 reversed ovarian impairment and fertility of aged mice in vivo. We show that the age-related reduction in the expression of TXN (thioredoxin) leads to ferroptosis in human and mouse GCs by blocking BNIP3L-dependent mitophagy. Exogenous activation of TXN could promote mitophagy, thereby clearing excessive ROS and inhibiting ferroptosis. These results suggest that anti-ferroptosis-related treatments may assist in treating aging-related reproductive disorders.

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Research summary

The paper claims that thioredoxin-1 can inhibit ferroptosis in granulosa cells to mitigate ovarian aging. This research addresses a potential root cause of aging-related reproductive dysfunction, which is relevant to longevity studies.

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