Rbbp7-mediated deacetylation of Acsl4 promotes ovarian aging by enhancing ferroptosis.

Abstract

The ovarian aging can lead to infertility, increase risk of diabetes, heart disease, and other serious problems. Ferroptosis is involved in the aging of various tissues. However, the mechanism underlying the role of ferroptosis in natural ovarian aging remains unclear. Here, we revealed the role of ferroptosis in ovarian aging and explore the intervention strategies for ovarian aging. Transcriptome data suggested that ferroptosis may be involved in ovarian aging. Through iron ion detection, Prussian blue staining, immunohistochemistry (IHC) staining and western blot (WB), we further confirmed that ferroptosis occurs in aging ovaries. Meanwhile, Acyl-CoA synthetase long-chain family member 4 (Acsl4) is highly expressed in senescent ovaries. We also found that the ferroptosis inhibitor Deferoxamine (DFO), Ferrostatin-1 (Fer-1) or the Acsl4 inhibitor Rosiglitazone (Rosi) inhibited ovarian aging and granulosa cell damage in vivo and in vitro. Further mechanistic studies have shown that Myeloid ectopic viral integration site 2 (Meis2) could cooperate with specificity protein 1 (SP1) to promote transcription of Acsl4 gene. Acetyl-proteomic analysis demonstrated that the acetylation level of K401 residue in Acsl4 (Acsl4-K401) was significantly reduced, and retinoblastoma binding protein 7 (Rbbp7) was identified via immunoprecipitation-mass spectrometry (IP-MS) as a direct mediator of Acsl4 deacetylation. Deacetylation of Acsl4-K401 can increase enzyme activity by promoting ATP binding. In conclusion, the increased expression level and the decreased acetylation level of Acsl4 protein promote ferroptosis, which in turn induces ovarian aging. Inhibiting ferroptosis or Acsl4 can alleviate ovarian aging. Our research has revealed a new mechanism of ovarian aging and provided potential new targets for alleviating it.