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

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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/664497v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1b97e8forg.highwire.dtl.DTLVardef@123f8d0org.highwire.dtl.DTLVardef@a44c61org.highwire.dtl.DTLVardef@92b32e_HPS_FORMAT_FIGEXP M_FIG C_FIG Key pointsO_LIFerroptosis signatures are upregulated in aged GCs from human and mouse ovaries C_LIO_LITXN is deregulated in aged GCs, leading to mitochondrial and ROS metabolic dysfunction C_LIO_LITXN binds to DNA to regulate autophagy and mitophagy genes, including BNIP3L C_LIO_LIInhibition of ferroptosis can ameliorate GC dysfunction C_LI