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Updated: Oct 13, 2025
Improved Rodent Model of Myocardial Ischemia and Reperfusion Injury
Published on: March 7, 2022
Mitochondrial redox regulation and myocardial ischemia-reperfusion injury
Chwen-Lih Chen1, Liwen Zhang2, Zhicheng Jin3
1Department of Integrative Medical Sciences, College of Medicine, Northeast Ohio Medical University, Rootstown, Ohio.
Abstract:
Mitochondrial reactive oxygen species (ROS) have emerged as an important mechanism of disease and redox signaling in the cellular system. Under basal or pathological conditions, electron leakage for ROS production is primarily mediated by complexes I and III of the electron transport chain (ETC) and by the proton motive force (PMF), consisting of a membrane potential (ΔΨ) and a proton gradient (ΔpH). Several factors control redox status in mitochondria, including ROS, the PMF, oxidative posttranslational modifications (OPTM) of the ETC subunits, SOD2, and cytochrome c heme lyase (HCCS). In the mitochondrial PMF, increased ΔpH-supported backpressure due to diminishing electron transport and chemiosmosis promotes a more reductive mitochondrial physiological setting. OPTM by protein cysteine sulfonation in complex I and complex III has been shown to affect enzymatic catalysis, the proton gradient, redox status, and enzyme-mediated ROS production. Pathological conditions associated with oxidative or nitrosative stress, such as myocardial ischemia and reperfusion (I/R), increase mitochondrial ROS production and redox dysfunction via oxidative injury to complexes I and III, intensely enhancing protein cysteine sulfonation and impairing heme integrity. The physiological conditions of reductive stress induced by gains in SOD2 function normalize I/R-mediated ROS overproduction and redox dysfunction. Further insight into the cellular mechanisms by which HCCS, biogenesis of c-type cytochrome, and OPTM regulate PMF and ROS production in mitochondria will enrich our understanding of redox signal transduction and identify new therapeutic targets for cardiovascular diseases in which oxidative stress perturbs normal redox signaling.
Insights
Mitochondrial reactive oxygen species (ROS) are key in disease and cell signaling. Factors like electron transport chain complexes and proton motive force influence ROS production and redox balance, impacting cardiovascular health.
Area of Science:
- Mitochondrial biochemistry and redox signaling
- Cardiovascular pathophysiology
- Cellular redox homeostasis
Background:
- Mitochondrial reactive oxygen species (ROS) play critical roles in cellular signaling and disease pathogenesis.
- Electron transport chain (ETC) complexes I and III, along with proton motive force (PMF), are primary sites of ROS production.
- Redox status is modulated by ROS, PMF, oxidative posttranslational modifications (OPTM), SOD2, and cytochrome c heme lyase (HCCS).
Purpose of the Study:
- To elucidate the mechanisms regulating mitochondrial ROS production and redox signaling.
- To investigate the role of OPTM, particularly protein cysteine sulfonation, in mitochondrial function and dysfunction.
- To explore the therapeutic potential of targeting redox pathways in cardiovascular diseases.
Main Methods:
- Analysis of mitochondrial electron transport chain (ETC) function and ROS production.
- Investigation of oxidative posttranslational modifications (OPTM) in mitochondrial proteins.
- Assessment of the impact of SOD2 and HCCS on mitochondrial redox state and ROS levels.
- Modeling of myocardial ischemia-reperfusion (I/R) injury to study redox dysfunction.
Main Results:
- Increased ΔpH in the mitochondrial PMF contributes to a more reductive cellular environment.
- Protein cysteine sulfonation in ETC complexes I and III affects enzymatic activity, PMF, and ROS generation.
- Myocardial I/R injury exacerbates mitochondrial ROS production and redox dysfunction through oxidative damage and sulfonation.
- Enhanced SOD2 function under reductive stress conditions mitigates I/R-induced ROS overproduction.
Conclusions:
- Mitochondrial ROS production and redox signaling are tightly regulated by ETC, PMF, and OPTM.
- Protein cysteine sulfonation is a key mechanism linking oxidative stress to mitochondrial dysfunction in cardiovascular disease.
- Targeting HCCS, cytochrome c biogenesis, and OPTM pathways may offer novel therapeutic strategies for redox-related cardiovascular disorders.
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