Related Experiment Video
Updated: Sep 10, 2025
Protection of H9c2 Myocardial Cells from Oxidative Stress by Crocetin via PINK1/Parkin Pathway-Mediated Mitophagy
Published on: May 26, 2023
SIRT3 attenuates sepsis-induced EndMT and cardiac remodeling by facilitating mitophagy process via PINK1/Parkin
Penghao Liu1, Tianhua Xu2, Yujun Luo1
1Department of Anesthesiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
Objective:
Endothelial-mesenchymal transition (EndMT) is a key contributor to the progression of sepsis-induced myocardial injury (SIMI). Defective mitophagy can result in oxidative stress and mitochondrial dysfunction, both of which play a critical role in EndMT. Sirtuin 3 (SIRT3), a major deacetylase responsible for mitochondrial quality control, has the potential to regulate EndMT, although the exact mechanism remains unclear. Therefore, this study aims to investigate the role of SIRT3 in mediating EndMT and cardiac remodeling during SIMI.
Methods:
Wild-type and SIRT3 knockout mice were induced with lipopolysaccharide (LPS) for 24-h to mimic SIMI. Human cardiac microvascular endothelial cells were treated with LPS for in vitro experiments. Cardiac function was measured by echocardiography. Cardiac fibrosis was determined by Sirus red and Masson's trichrome staining. The expression of endothelial biomarkers and mesenchymal biomarkers was detected using immunofluorescence and western blot to determine EndMT. Mitochondria function and mitophagy were determined by transmission electron microscopy (TEM) and protein biomarkers. The interaction of SIRT3 with PINK1/Parkin was detected by immunoprecipitation (IP) and co-IP.
Results:
Following endotoxin exposure, SIRT3 knockout mice exhibited a more severe EndMT phenotype and increased collagen deposition in cardiac tissues, along with mitochondrial dysfunction and impaired mitophagy. Similarly, LPS treatment induced mitochondrial oxidative stress and disrupted mitophagy flux during EndMT in CMECs, effects that were partially rescued by either rapamycin treatment or SIRT3 upregulation. Furthermore, SIRT3 overexpression enhanced deacetylation of the PINK1/Parkin pathway, thereby promoting mitophagy.
Conclusion:
Our findings suggest that SIRT3 suppresses EndMT-mediated cardiac fibrosis by promoting PINK1/Parkin-dependent mitophagy, offering novel insights for the treatment of SIMI.
Insights
Sirtuin 3 (SIRT3) suppresses sepsis-induced myocardial injury by enhancing mitophagy, thereby reducing cardiac fibrosis and endothelial-mesenchymal transition. This study clarifies SIRT3's role in mitochondrial quality control during sepsis.
Area of Science:
- Cardiovascular Biology
- Mitochondrial Biology
- Sepsis Research
Background:
- Endothelial-mesenchymal transition (EndMT) drives sepsis-induced myocardial injury (SIMI).
- Defective mitophagy contributes to oxidative stress and mitochondrial dysfunction, exacerbating EndMT.
- Sirtuin 3 (SIRT3) is a key mitochondrial deacetylase, but its role in SIMI-induced EndMT is unclear.
Purpose of the Study:
- To investigate the role of SIRT3 in mediating EndMT and cardiac remodeling during SIMI.
- To elucidate the mechanism by which SIRT3 influences mitochondrial quality control in the context of sepsis.
Main Methods:
- Lipopolysaccharide (LPS) induced SIMI in wild-type and SIRT3 knockout mice.
- In vitro studies used LPS-treated human cardiac microvascular endothelial cells (CMECs).
- Assessed cardiac function, fibrosis, EndMT markers, mitochondrial function, mitophagy, and SIRT3 interactions with PINK1/Parkin.
Main Results:
- SIRT3 knockout mice showed exacerbated EndMT, cardiac fibrosis, mitochondrial dysfunction, and impaired mitophagy post-LPS.
- LPS induced oxidative stress and disrupted mitophagy in CMECs, partially rescued by rapamycin or SIRT3.
- SIRT3 overexpression promoted mitophagy via deacetylation of the PINK1/Parkin pathway.
Conclusions:
- SIRT3 mitigates EndMT-mediated cardiac fibrosis in SIMI by enhancing PINK1/Parkin-dependent mitophagy.
- SIRT3 represents a potential therapeutic target for treating sepsis-induced myocardial injury.
