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Updated: May 24, 2026
Improved Rodent Model of Myocardial Ischemia and Reperfusion Injury
Published on: March 7, 2022
SIRT3-mediated deacetylation of ATP5A1 improves mitochondrial function to attenuate myocardial ischemia-reperfusion
Yuanyuan Chen1, Gaojie Xin2, Huiyu Zhang1
1Institute of Basic Medicine, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China.
Abstract:
Mitochondrial dysfunction represents a core pathological feature of myocardial ischemia-reperfusion injury (MIRI). Protein acetylation plays a crucial role in regulating mitochondrial function; however, its precise molecular mechanisms in MIRI remain incompletely elucidated. In this study, we performed bioinformatics analysis to screen for differentially expressed genes (DEGs) in MIRI-related datasets (GSE83472, GSE58486, and GSE61592). By integrating these DEGs with mitochondrial gene sets, sirtuin 3 (SIRT3) was identified as a core regulatory molecule. Subsequently, we used SIRT3 inhibitors or plasmid transfection to downregulate or overexpress SIRT3 in MIRI mice and H/R-injured HL-1 cardiomyocytes. The effects of SIRT3 on mitochondrial function and its mediated deacetylation of ATP synthase F1 complex subunit alpha (ATP5A1) on MIRI were evaluated through biochemical assays, histopathology, electron microscopy, immunoprecipitation, and point mutation analysis. Our results demonstrated that under MIRI conditions, SIRT3 expression was downregulated, leading to increased mitochondrial protein acetylation levels, impaired mitochondrial structure, and elevated cardiomyocyte apoptosis. Furthermore, inhibiting SIRT3 expression exacerbated mitochondrial damage and MIRI. Overexpression of SIRT3 significantly reduced ATP5A1 acetylation, restored mitochondrial membrane potential, decreased reactive oxygen species (ROS) production, enhanced mitochondrial respiration, and inhibited cardiomyocyte apoptosis. In summary, SIRT3 improves mitochondrial function by mediating ATP5A1 deacetylation, thereby alleviating MIRI. This finding reveals a novel molecular mechanism and provides a potential therapeutic target for the treatment of MIRI.
Insights
Sirtuin 3 (SIRT3) protects against myocardial ischemia-reperfusion injury (MIRI) by deacetylating ATP synthase. Restoring SIRT3 function mitigates mitochondrial dysfunction and cardiomyocyte apoptosis in MIRI.
Area of Science:
- Cardiovascular Biology
- Mitochondrial Medicine
- Molecular Cardiology
Background:
- Mitochondrial dysfunction is central to myocardial ischemia-reperfusion injury (MIRI).
- The role of protein acetylation in MIRI pathogenesis is not fully understood.
- Sirtuin 3 (SIRT3) is a key regulator of mitochondrial function.
Purpose of the Study:
- To investigate the role of SIRT3 in MIRI.
- To elucidate the molecular mechanisms by which SIRT3 regulates mitochondrial function in MIRI.
- To evaluate SIRT3 as a potential therapeutic target for MIRI.
Main Methods:
- Bioinformatics analysis of MIRI datasets (GSE83472, GSE58486, GSE61592) to identify differentially expressed genes.
- In vivo and in vitro experiments using SIRT3 inhibitors/plasmids in MIRI mouse models and H/R-injured HL-1 cardiomyocytes.
- Biochemical assays, histopathology, electron microscopy, immunoprecipitation, and point mutation analysis to assess mitochondrial function and ATP5A1 acetylation.
Main Results:
- SIRT3 expression was downregulated in MIRI, leading to increased mitochondrial acetylation, structural damage, and apoptosis.
- SIRT3 inhibition worsened MIRI outcomes.
- SIRT3 overexpression reduced ATP5A1 acetylation, improved mitochondrial potential and respiration, decreased reactive oxygen species (ROS), and protected against cardiomyocyte apoptosis.
Conclusions:
- SIRT3 mitigates MIRI by deacetylating ATP synthase F1 complex subunit alpha (ATP5A1), thereby enhancing mitochondrial function.
- SIRT3 represents a novel therapeutic target for MIRI treatment.
- This study reveals a critical molecular mechanism linking protein acetylation to MIRI pathogenesis.
