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Reduction of elevated proton leak rejuvenates mitochondria in the aged cardiomyocyte
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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738186/ https://www.ncbi.nlm.nih.gov/pubmed/33319746 http://dx.doi.org/10.7554/eLife.60827 |
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author | Zhang, Huiliang Alder, Nathan N Wang, Wang Szeto, Hazel Marcinek, David J Rabinovitch, Peter S |
author_facet | Zhang, Huiliang Alder, Nathan N Wang, Wang Szeto, Hazel Marcinek, David J Rabinovitch, Peter S |
author_sort | Zhang, Huiliang |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7738186 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-77381862020-12-16 Reduction of elevated proton leak rejuvenates mitochondria in the aged cardiomyocyte Zhang, Huiliang Alder, Nathan N Wang, Wang Szeto, Hazel Marcinek, David J Rabinovitch, Peter S eLife Cell Biology 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. eLife Sciences Publications, Ltd 2020-12-15 /pmc/articles/PMC7738186/ /pubmed/33319746 http://dx.doi.org/10.7554/eLife.60827 Text en © 2020, Zhang et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cell Biology Zhang, Huiliang Alder, Nathan N Wang, Wang Szeto, Hazel Marcinek, David J Rabinovitch, Peter S Reduction of elevated proton leak rejuvenates mitochondria in the aged cardiomyocyte |
title | Reduction of elevated proton leak rejuvenates mitochondria in the aged cardiomyocyte |
title_full | Reduction of elevated proton leak rejuvenates mitochondria in the aged cardiomyocyte |
title_fullStr | Reduction of elevated proton leak rejuvenates mitochondria in the aged cardiomyocyte |
title_full_unstemmed | Reduction of elevated proton leak rejuvenates mitochondria in the aged cardiomyocyte |
title_short | Reduction of elevated proton leak rejuvenates mitochondria in the aged cardiomyocyte |
title_sort | reduction of elevated proton leak rejuvenates mitochondria in the aged cardiomyocyte |
topic | Cell Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738186/ https://www.ncbi.nlm.nih.gov/pubmed/33319746 http://dx.doi.org/10.7554/eLife.60827 |
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