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SIRT1-mediated deacetylation of DRP1 suppresses excessive mitophagy and ameliorates pediatric functional dyspepsia
Shuan Yin1, Dongdong Dai2, Gaoyan Wang1
1Department of Pediatrics, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
Insights
SIRT1 protects against functional dyspepsia (FD) in children by regulating mitophagy and mitochondrial function. This study highlights the SIRT1-DRP1 pathway as a potential therapeutic target for pediatric FD.
Area of Science:
- Gastroenterology
- Molecular Biology
- Cell Biology
Background:
- Functional dyspepsia (FD) is common in children, with unclear molecular causes.
- Mitochondrial dysfunction and excessive mitophagy are suspected contributors to pediatric FD.
- The role of SIRT1 in FD's mitochondrial quality control needs further investigation.
Purpose of the Study:
- To investigate the role of SIRT1 in mitochondrial quality control in pediatric FD.
- To explore the therapeutic potential of SIRT1 in pediatric FD.
- To elucidate the molecular mechanisms linking SIRT1, mitophagy, and inflammation in FD.
Main Methods:
- Analyzed SIRT1 expression and inflammatory cytokines in pediatric FD patient serum.
- Induced mitochondrial stress in human gastric smooth muscle cells (HGSMCs) using CCCP.
- Assessed mitochondrial function, mitophagy, oxidative stress, and protein interactions via qPCR, Western blot, co-immunoprecipitation, and functional assays.
Main Results:
- SIRT1 was downregulated in pediatric FD patients and CCCP-treated HGSMCs, correlating with increased IL-6, TNF-α, and IL-1β.
- SIRT1 overexpression improved cell viability, ATP production, and mitochondrial membrane potential, while reducing mitophagy and oxidative stress.
- SIRT1 deacetylated DRP1 at K283, promoting its degradation and inhibiting excessive mitophagy and oxidative stress, findings confirmed by DRP1 knockdown and overexpression rescue experiments.
Conclusions:
- SIRT1 plays a protective role in pediatric FD by targeting the SIRT1-DRP1 axis.
- SIRT1 ameliorates mitochondrial dysfunction and oxidative stress by inhibiting excessive mitophagy via DRP1 deacetylation.
- The SIRT1-DRP1 pathway represents a promising therapeutic target for pediatric FD.
Abstract:
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.
