Mitochondrial DNA leakage in oocytes activates cGAS-STING signaling to drive ovarian aging.

Ovarian aging precedes decline in many organs, but its mechanisms remain unclear. Here we show that aging oocytes accumulate cytoplasmic mitochondrial DNA (mtDNA) through increased mtDNA leakage, activating the cyclic GMP-AMP synthase (cGAS) pathway to produce cGAMP and trigger stimulator of interferon genes (STING) signaling. Notably, oocyte-derived cGAMP can pass through gap junctions to surrounding granulosa cells (GCs), activating STING signaling in GCs as well. To model age-associated mitochondrial dysfunction, we generated oocyte-specific Tfam-knockout mice, which recapitulated mtDNA leakage, STING pathway activation in both oocytes and GCs, inflammation and accelerated ovarian dysfunction. We also used Opa1 knockdown and Pink1 deletion oocytes as complementary mitochondrial stress models and observed mtDNA leakage and cGAS-STING activation in both settings. Notably, oocyte-specific Cgas deletion in Tfam mutants or pharmacological STING inhibition with H-151 ameliorated ovarian dysfunction. These findings establish oocyte mtDNA leakage as a causal driver of ovarian aging and nominate cGAS-STING signaling as a therapeutic target.