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

Aging Cell
Nicola ManzellaJeanne Mialet-Perez

Abstract

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 H2 O2 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 p21cip , p16ink4a , and p15ink4b 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 impor...Continue Reading

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Jan 25, 2020·Cell Death & Disease·Jeanne Mialet-Perez, Angelo Parini
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Methods Mentioned

BETA
deamination
PCR
ubiquitination
transfection
transfections
immunoprecipitation
electrophoresis
column affinity purification

Software Mentioned

Lab
Image

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