Propionate Induces Intestinal Oxidative Stress Via SOD2 Propionylation

Propionate and propionyl-CoA accumulation have been associated with mitochondrial dysfunction. In this study, we observed that propionate induced intestinal damage in the context of high fat diet (HFD) in zebrafish. The intestinal damage was associated with oxidative stress and mitochondrial dysfunction owing to compromised SOD2 activity and the resultant impairment of antioxidant capacity. Global lysine propionylation analysis of the intestinal samples showed that SOD2 was propionylated at lysine 132, and further biochemical assays demonstrated that lysine 132 propionylation suppressed SOD2 activity. In addition, SIRT3 played an important role in regulating SOD2 activity via modulating depropionylation, and the enhanced SOD2 propionylation in zebrafish fed high fat plus propionate diet was attributable to reduced SIRT3 expression. Finally, we reveal that intestinal oxidative stress resulting from SOD2 propionylation contributed to the compositional change of gut microbiota, which further deteriorated intestinal oxidative stress independent of SIRT3. Collectively, the results in this study reveal a link between SOD2 propionylation and oxidative stress, and highlight the potential mechanism of intestinal problems associated with high propionate level.