mtDNA Leakage From Oocytes Drives Ovarian Aging; Blocking It Restores Reproductive Function

A study has found that leakage of mitochondrial DNA (mtDNA) from oocytes drives ovarian aging. Inhibiting this signaling pathway was found to restore reproductive function in aged mice.

A research team led by Yang Qingling of Zhengzhou University in China published the findings Aug. 28 (local time) in the journal Nature Aging.

The ovaries age earlier than other organs. Follicle numbers decline, oocyte quality deteriorates and chronic inflammation increases. However, the specific mechanisms that cause ovarian aging have not been clearly established.

The research team focused on the fact that oocytes are the largest cells in the body and are rich in mitochondria. Oocytes rely on mitochondrial health to support fertilization and early embryonic development, but their limited capacity to repair mtDNA makes them vulnerable to age-related functional decline.

The study found that in aged oocytes, mtDNA leaked into the cytoplasm and activated an innate immune signaling pathway called cGAS-STING. This pathway normally detects external threats such as viruses.

The signaling molecule cGAMP produced in oocytes passed through intercellular channels to nearby granulosa cells, triggering an inflammatory response. The research team confirmed that mtDNA leakage, inflammation and impaired ovarian function were reproduced in a mouse model in which the Tfam gene was specifically deleted in oocytes.

Conversely, deleting the Cgas gene in these mice or blocking STING signaling with the drug H-151 improved ovarian dysfunction. The research team said that mtDNA leakage from oocytes is a direct cause of ovarian aging and that cGAS-STING signaling could be a therapeutic target.