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Reduction of elevated proton leak rejuvenates mitochondria in the aged cardiomyocyte

Citation

Zhang, Huiliang et al. (2020), Reduction of elevated proton leak rejuvenates mitochondria in the aged cardiomyocyte, Dryad, Dataset, https://doi.org/10.5061/dryad.fqz612jqs

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 is able to reverse this clinically important complication of cardiac aging.

Methods

Mitochondrial respiration data were collected by Seahorse Assay and combined all the data in the attached excel file.

Confocal imaging data were collceted by Leica SP8X and images were analyzed by the Leica LASX or FIJI software. 

The western blot images were collected by FluoChem Q machine and analyzed by AlphaView software.

Funding

National Institute on Aging, Award: P01AG001751

National Institute on Aging, Award: R56AG055114

National Heart, Lung, and Blood Institute, Award: 114760

National Heart, Lung, and Blood Institute, Award: 137266

American Heart Association, Award: 18EIA33900041

American Heart Association, Award: 19CDA34660311

Glenn Foundation for Medical Research, Award: Postdoctoral Fellowship