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Updated: Nov 25, 2025
A Flow Cytometry-based Assay for Measuring Mitochondrial Membrane Potential in Cardiac Myocytes After Hypoxia/Reoxygenation
Published on: July 13, 2018
Reduction of elevated proton leak rejuvenates mitochondria in the aged cardiomyocyte
Huiliang Zhang1, Nathan N Alder2, Wang Wang1,3
1Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States.
Insights
Aging hearts show increased proton leak, a key factor in cardiac dysfunction. The peptide SS-31 reverses this by rejuvenating mitochondria, offering a potential treatment for age-related heart problems.
Area of Science:
- Mitochondrial Physiology
- Cardiovascular Aging
- Molecular Cardiology
Background:
- Physiologic aging and cardiac aging mechanisms are poorly understood.
- Age-related heart impairment lacks effective clinical treatments.
- Increased proton leak in aged heart mitochondria is a novel finding.
Purpose of the Study:
- To investigate the mechanisms of cardiac aging.
- To identify the molecular basis of increased proton leak in aged hearts.
- To evaluate the therapeutic potential of SS-31 in reversing cardiac aging.
Main Methods:
- Utilized naturally aging mice and rats as models.
- Measured mitochondrial proton leak in aged heart cells.
- Investigated the role of ANT1 in mitochondrial permeability.
- Assessed the effects of SS-31 on mitochondrial function and cardiac diastolic dysfunction.
Main Results:
- Demonstrated increased proton leak in aged heart mitochondria.
- Identified ANT1 as a likely mediator of increased mitochondrial proton permeability.
- SS-31 prevented excess proton entry and reduced mitochondrial dysfunction.
- SS-31 treatment reversed age-related diastolic dysfunction.
Conclusions:
- Excessive proton leak is a novel mechanism of age-related cardiac dysfunction.
- SS-31 rejuvenates mitochondrial function by interacting with ANT1 and ATP synthasome.
- SS-31 shows potential for reversing cardiac aging complications.
Abstract:
Aging-associated diseases, including cardiac dysfunction, are increasingly common in the population. However, the mechanisms of physiologic aging in general, and cardiac aging in particular, remain poorly understood. Age-related heart impairment is lacking a clinically effective treatment. Using the model of naturally aging mice and rats, we show direct evidence of increased proton leak in the aged heart mitochondria. Moreover, our data suggested ANT1 as the most likely site of mediating increased mitochondrial proton permeability in old cardiomyocytes. Most importantly, the tetra-peptide SS-31 prevents age-related excess proton entry, decreases the mitochondrial flash activity and mitochondrial permeability transition pore opening, rejuvenates mitochondrial function by direct association with ANT1 and the mitochondrial ATP synthasome, and leads to substantial reversal of diastolic dysfunction. Our results uncover the excessive proton leak as a novel mechanism of age-related cardiac dysfunction and elucidate how SS-31 can reverse this clinically important complication of cardiac aging.
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