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Monoamine oxidase‐A is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy

Cellular senescence, the irreversible cell cycle arrest observed in somatic cells, is an important driver of age‐associated diseases. Mitochondria have been implicated in the process of senescence, primarily because they are both sources and targets of reactive oxygen species (ROS). In the heart, ox...

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Autores principales: Manzella, Nicola, Santin, Yohan, Maggiorani, Damien, Martini, Hélène, Douin‐Echinard, Victorine, Passos, Joao F., Lezoualc'h, Frank, Binda, Claudia, Parini, Angelo, Mialet‐Perez, Jeanne
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156293/
https://www.ncbi.nlm.nih.gov/pubmed/30003648
http://dx.doi.org/10.1111/acel.12811
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author Manzella, Nicola
Santin, Yohan
Maggiorani, Damien
Martini, Hélène
Douin‐Echinard, Victorine
Passos, Joao F.
Lezoualc'h, Frank
Binda, Claudia
Parini, Angelo
Mialet‐Perez, Jeanne
author_facet Manzella, Nicola
Santin, Yohan
Maggiorani, Damien
Martini, Hélène
Douin‐Echinard, Victorine
Passos, Joao F.
Lezoualc'h, Frank
Binda, Claudia
Parini, Angelo
Mialet‐Perez, Jeanne
author_sort Manzella, Nicola
collection PubMed
description Cellular senescence, the irreversible cell cycle arrest observed in somatic cells, is an important driver of age‐associated diseases. Mitochondria have been implicated in the process of senescence, primarily because they are both sources and targets of reactive oxygen species (ROS). In the heart, oxidative stress contributes to pathological cardiac ageing, but the mechanisms underlying ROS production are still not completely understood. The mitochondrial enzyme monoamine oxidase‐A (MAO‐A) is a relevant source of ROS in the heart through the formation of H(2)O(2) derived from the degradation of its main substrates, norepinephrine (NE) and serotonin. However, the potential link between MAO‐A and senescence has not been previously investigated. Using cardiomyoblasts and primary cardiomyocytes, we demonstrate that chronic MAO‐A activation mediated by synthetic (tyramine) and physiological (NE) substrates induces ROS‐dependent DNA damage response, activation of cyclin‐dependent kinase inhibitors p21(cip), p16(ink4a), and p15(ink4b) and typical features of senescence such as cell flattening and SA‐β‐gal activity. Moreover, we observe that ROS produced by MAO‐A lead to the accumulation of p53 in the cytosol where it inhibits parkin, an important regulator of mitophagy, resulting in mitochondrial dysfunction. Additionally, we show that the mTOR kinase contributes to mitophagy dysfunction by enhancing p53 cytoplasmic accumulation. Importantly, restoration of mitophagy, either by overexpression of parkin or inhibition of mTOR, prevents mitochondrial dysfunction and induction of senescence. Altogether, our data demonstrate a novel link between MAO‐A and senescence in cardiomyocytes and provides mechanistic insights into the potential role of MAO‐dependent oxidative stress in age‐related pathologies.
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spelling pubmed-61562932018-10-01 Monoamine oxidase‐A is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy Manzella, Nicola Santin, Yohan Maggiorani, Damien Martini, Hélène Douin‐Echinard, Victorine Passos, Joao F. Lezoualc'h, Frank Binda, Claudia Parini, Angelo Mialet‐Perez, Jeanne Aging Cell Original Paper Cellular senescence, the irreversible cell cycle arrest observed in somatic cells, is an important driver of age‐associated diseases. Mitochondria have been implicated in the process of senescence, primarily because they are both sources and targets of reactive oxygen species (ROS). In the heart, oxidative stress contributes to pathological cardiac ageing, but the mechanisms underlying ROS production are still not completely understood. The mitochondrial enzyme monoamine oxidase‐A (MAO‐A) is a relevant source of ROS in the heart through the formation of H(2)O(2) derived from the degradation of its main substrates, norepinephrine (NE) and serotonin. However, the potential link between MAO‐A and senescence has not been previously investigated. Using cardiomyoblasts and primary cardiomyocytes, we demonstrate that chronic MAO‐A activation mediated by synthetic (tyramine) and physiological (NE) substrates induces ROS‐dependent DNA damage response, activation of cyclin‐dependent kinase inhibitors p21(cip), p16(ink4a), and p15(ink4b) and typical features of senescence such as cell flattening and SA‐β‐gal activity. Moreover, we observe that ROS produced by MAO‐A lead to the accumulation of p53 in the cytosol where it inhibits parkin, an important regulator of mitophagy, resulting in mitochondrial dysfunction. Additionally, we show that the mTOR kinase contributes to mitophagy dysfunction by enhancing p53 cytoplasmic accumulation. Importantly, restoration of mitophagy, either by overexpression of parkin or inhibition of mTOR, prevents mitochondrial dysfunction and induction of senescence. Altogether, our data demonstrate a novel link between MAO‐A and senescence in cardiomyocytes and provides mechanistic insights into the potential role of MAO‐dependent oxidative stress in age‐related pathologies. John Wiley and Sons Inc. 2018-07-12 2018-10 /pmc/articles/PMC6156293/ /pubmed/30003648 http://dx.doi.org/10.1111/acel.12811 Text en © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Paper
Manzella, Nicola
Santin, Yohan
Maggiorani, Damien
Martini, Hélène
Douin‐Echinard, Victorine
Passos, Joao F.
Lezoualc'h, Frank
Binda, Claudia
Parini, Angelo
Mialet‐Perez, Jeanne
Monoamine oxidase‐A is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy
title Monoamine oxidase‐A is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy
title_full Monoamine oxidase‐A is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy
title_fullStr Monoamine oxidase‐A is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy
title_full_unstemmed Monoamine oxidase‐A is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy
title_short Monoamine oxidase‐A is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy
title_sort monoamine oxidase‐a is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy
topic Original Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156293/
https://www.ncbi.nlm.nih.gov/pubmed/30003648
http://dx.doi.org/10.1111/acel.12811
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