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

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 H2O2 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 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.

P53 and Parkin co-regulate mitophagy in bone marrow mesenchymal stem cells to promote the repair of early steroid-induced osteonecrosis of the femoral head

“…Data were compared with the XACB/BMSCs/Parkin and XACB/BMSCs/shP53 groups: # P < 0.05. mammalian target of rapamycin (mTOR) pathways 26,27 . After its expression is upregulated, P53 can bind to the RING0 region of Parkin and then interfere with Parkin's biological function 30,31 . Whether this is also true in BMSCs requires further study.…”

“…4o-q). Recent studies have shown that P53 can bind to Parkin and interfere with its physiological functions [29][30][31] . This may interfere with Parkin-mediated mitophagy, limiting the ability of Parkin upregulation alone to enhance mitophagy.…”

“…OS can upregulate the expression of P53 in cells 40,41 . Some studies have shown that P53 can interact with Parkin's RING0 region 30,31 . The PINK1-Parkin pathway is the most important pathway by which mitophagy is mediated 42 ; therefore, to further study whether P53 regulated mitophagy via this pathway, we continued to treat BMSCs for 24 h using an H 2 O 2 (1000 μM)-simulated OS.…”

“…It is well known that OS can lead to upregulation of P53 [25][26][27][28] . In addition, recent studies have shown that P53 can bind to Parkin's Really Interesting New Gene 0 (RING0) region, which interferes with Parkin's biological function, affecting mitochondrial quality control, biosynthesis, kinetic regulation, and cellular redox homeostasis 19,[29][30][31] . Parkin's main function in mitochondrial quality control is to label damaged mitochondria via ubiquitin ligase activity, which, in turn, mediates mitophagy.…”

Clearance of senescent cells following cardiac ischemia-reperfusion injury improves recovery

“…9 A key component of IRI is the increased generation of reactive oxygen species 10 which is thought to contribute to tissue dysfunction. Previously, we had shown that cardiomyocyte (CM) senescence can be induced by oxidative stress associated with aging 11,12 and contributes to age-related myocardial remodelling. 11 We, therefore, hypothesized that cellular senescence may be an outcome of the oxidative burst occurring during cardiac IRI and be a key contributor to its associated adverse ventricular remodeling and impaired cardiac function.…”