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Monoamine oxidase-A is a novel driver of stress-induced premature senescence through inhibition of parkin-mediated mitophagy
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Edité par CCSD ; Wiley Open Access -
International audience. 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 cyto-sol where it inhibits parkin, an important regulator of mitophagy, resulting in mito-chondrial 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 oxida-tive stress in age-related pathologies.
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