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

• DOI: 10.1111/acel.12811
• Publication Date: 2018-07-13T05:50:59Z
• Authors: Nicola Manzella; Yohan Santin; Damien Maggiorani; Hélène Martini; Victorine Douin‐E...; Joao F. Passos; Frank Lezoualc'h; Claudia Binda; Angelo Parini; Jeanne Mialet‐Perez
• Keywords: Senescence; Mitochondrial ROS

Abstract Cellular senescence, the irreversible cell cycle arrest observed in somatic cells, is an important driver of age‐associated diseases. Mitochondria have been implicated process primarily because they are both sources and targets reactive oxygen species (ROS). In heart, oxidative stress contributes to pathological cardiac ageing, but mechanisms underlying ROS production still not completely understood. The mitochondrial enzyme monoamine oxidase‐A (MAO‐A) a relevant source heart through formation H 2 O derived from degradation its main substrates, norepinephrine (NE) serotonin. However, potential link between MAO‐A senescence has previously investigated. Using cardiomyoblasts primary cardiomyocytes, we demonstrate that chronic activation mediated by synthetic (tyramine) physiological substrates induces ROS‐dependent DNA damage response, cyclin‐dependent kinase inhibitors p21 cip , p16 ink4a p15 ink4b typical features such as flattening SA‐β‐gal activity. Moreover, observe produced lead accumulation p53 cytosol where it inhibits parkin, regulator mitophagy, resulting dysfunction. Additionally, show mTOR mitophagy dysfunction enhancing cytoplasmic accumulation. Importantly, restoration either overexpression parkin or inhibition mTOR, prevents induction senescence. Altogether, our data novel cardiomyocytes provides mechanistic insights into role MAO‐dependent age‐related pathologies.