SIRT2-dependent SQSTM1 decrotonylation at K100 rescues impaired mitophagy in aged bovine oocytes.

Aging-associated defects in oocyte in vitro maturation limit the applications of assisted reproductive technologies in aged females breeding cows. In this study, SIRT2 protein levels were significantly down-regulated in aged bovine oocytes, accompanied by impaired mitochondrial function. Microinjection of SIRT2 mRNA ameliorated maturation failure in aged bovine oocytes, while restoring mitochondrial function and mitophagy. Mechanistically, we demonstrated that SIRT2 mediated the decrotonylation of SQSTM1 at lysine 100. Decrotonylation of SQSTM1 at K100 facilitated its interaction with LC3B, thereby accelerating lysosomal degradation of age-associated damaged mitochondria. Consistently, SQSTM1 decrotonylation at lysine 100 enhanced mitophagy and rescued maturation defects in maternally aged oocytes, and this protective effect was independent of SQSTM1 hypercrotonylation. Our findings reveal a novel mechanism underlying oocyte aging and identify a promising molecular target for improving oocyte maturation in aged elite cattle.