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Reduction of elevated proton leak rejuvenates mitochondria in the aged cardiomyocyte.
- Source :
-
ELife [Elife] 2020 Dec 15; Vol. 9. Date of Electronic Publication: 2020 Dec 15. - Publication Year :
- 2020
-
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.<br />Competing Interests: HZ, NA, WW, DM, PR No competing interests declared, HS is the inventor of SS-31 and founder of Stealth Biotherapeutics.<br /> (© 2020, Zhang et al.)
- Subjects :
- Adenine Nucleotide Translocator 1 metabolism
Adenosine Triphosphate metabolism
Age Factors
Aging
Animals
Cells, Cultured
Energy Metabolism drug effects
Hydrogen-Ion Concentration
Membrane Potentials
Mice, Inbred C57BL
Mice, Transgenic
Mitochondria, Heart metabolism
Mitochondrial Permeability Transition Pore antagonists & inhibitors
Mitochondrial Permeability Transition Pore metabolism
Myocytes, Cardiac metabolism
Protons
Rats, Inbred F344
Reactive Oxygen Species metabolism
Adenine Nucleotide Translocator 1 antagonists & inhibitors
Cellular Senescence
Mitochondria, Heart drug effects
Myocytes, Cardiac pathology
Oligopeptides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 2050-084X
- Volume :
- 9
- Database :
- MEDLINE
- Journal :
- ELife
- Publication Type :
- Academic Journal
- Accession number :
- 33319746
- Full Text :
- https://doi.org/10.7554/eLife.60827