Functional dyspepsia (FD) is a prevalent gastrointestinal disorder in children, but its underlying molecular mechanisms remain poorly understood. Mitochondrial dysfunction and excessive mitophagy have been implicated in FD, but the underlying mechanisms remain poorly understood. This study aimed to investigate the role of SIRT1 in mitochondrial quality control and its potential therapeutic value in pediatric FD. Serum samples from pediatric FD patients and healthy controls were analyzed for SIRT1 expression and inflammatory cytokines. Human gastric smooth muscle cells (HGSMCs) were treated with carbonyl cyanide m-chlorophenyl hydrazone (CCCP) to induce mitochondrial stress. Mitochondrial function, mitophagy, oxidative stress, and protein interactions were assessed using qPCR, Western blot, co-immunopcipitation, and functional assays including ATP levels, mitochondrial membrane potential, ROS, MDA, SOD, and GSH-Px. The results showed that SIRT1 was significantly downregulated in both pediatric FD patient sera and CCCP-stimulated HGSMCs, accompanied by elevated pro-inflammatory cytokines including IL-6, TNF-α, and IL-1β. Overexpression of SIRT1 improved cell viability, ATP production, mitochondrial membrane potential, and suppressed excessive mitophagy and oxidative stress. Conversely, DRP1 knockdown phenocopied the protective effects of SIRT1, reducing mitophagy and oxidative stress in CCCP-stimulated cells. SIRT1 directly interacted with DRP1 and promoted its deacetylation at lysine 283, leading to accelerated DRP1 degradation. Rescue experiments confirmed that DRP1 overexpression reversed the protective effects of SIRT1 on mitochondrial function and redox homeostasis. In conclusion, SIRT1 exerts protective effects in pediatric FD by deacetylating DRP1 at K283, thereby inhibiting excessive mitophagy and ameliorating mitochondrial dysfunction and oxidative stress. These findings identify the SIRT1-DRP1 axis as a potential therapeutic target for pediatric FD.
Yin et al. (Fri,) studied this question.