Inhibition of p53 preserves Parkin-mediated mitophagy and pancreatic β-cell function in diabetes

Hoshino, Atsushi; Ariyoshi, Makoto; Okawa, Yoshifumi; Kaimoto, Satoshi; Uchihashi, Motoki; Fukai, Kuniyoshi; Iwai-Kanai, Eri; Ikeda, Koji; Ueyama, Tomomi; Ogata, Toru; Matoba, Satoaki

doi:10.1073/pnas.1318951111

Cited by 190 publications

(160 citation statements)

References 32 publications

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“…Consistently, p53 knockdown prevented the decrease in mitochondrial membrane potential and inhibited mitochondrial ROS accumulation. Our results are in line with previous studies that show that the p53‐parkin inhibition pathway plays an important role in cardiac ageing and drives age‐related diseases, such as heart failure and diabetes (Hoshino et al, 2014, 2013 ). Notably, we provide additional mechanistic evidence that p53 is a major mediator of the MAO‐A‐dependent response.…”

Section: Discussionsupporting

confidence: 93%

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

et al. 2018

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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.

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Section: Discussionsupporting

confidence: 93%

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

et al. 2018

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“…Recently, a study reported that Parkin-mediated mitophagy is protective in pancreatic ␤-cell function in diabetes (30). Diabetic cardiomyopathy is associated with mitochondrial dysfunction (6), and it is possible that impaired autophagy and mitophagy may contribute to the pathology.…”

Section: H188mentioning

confidence: 99%

Mending a broken heart: the role of mitophagy in cardioprotection

Moyzis

Sadoshima

Gustafsson

2015

American Journal of Physiology-Heart and Circulatory Physiology

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Moyzis AG, Sadoshima J, Gustafsson ÅB. Mending a broken heart: the role of mitophagy in cardioprotection. Am J Physiol Heart Circ Physiol 308: H183-H192, 2015. First published November 25, 2014 doi:10.1152/ajpheart.00708.2014.-The heart is highly energy dependent with most of its energy provided by mitochondrial oxidative phosphorylation. Mitochondria also play a role in many other essential cellular processes including metabolite synthesis and calcium storage. Therefore, maintaining a functional population of mitochondria is critical for cardiac function. Efficient degradation and replacement of dysfunctional mitochondria ensures cell survival, particularly in terminally differentiated cells such as cardiac myocytes. Mitochondria are eliminated via mitochondrial autophagy or mitophagy. In the heart, mitophagy is an essential housekeeping process and required for cardiac homeostasis. Reduced autophagy and accumulation of impaired mitochondria have been linked to progression of heart failure and aging. In this review, we discuss the pathways that regulate mitophagy in cells and highlight the cardioprotective role of mitophagy in response to stress and aging. We also discuss the therapeutic potential of targeting mitophagy and directions for future investigation.autophagy; mitophagy; mitochondria; parkin; BNIP3; FUNDC1 THE HEART IS HIGHLY ENERGY dependent, and the majority of its energy is provided by mitochondrial oxidative phosphorylation. Mitochondria also play a role in many other cellular processes including metabolite synthesis and calcium storage (41). Hence, maintaining a functional population of mitochondria is critical for cardiac function. Damaged mitochondria produce less ATP, generate greater amounts of reactive oxygen species (ROS), and can activate apoptosis and/or necrosis. Thus efficient removal of dysfunctional mitochondria and biogenesis of functional mitochondria are critical for the maintenance of cellular homeostasis. This is of particular importance in cells such as cardiac myocytes, which are terminally differentiated. The mechanism that the cell uses to eliminate damaged mitochondria is known as mitochondrial autophagy or mitophagy, and involves selective sequestering of the organelle inside an autophagosome and subsequent fusion with a lysosome where degradation occurs (98). Autophagy was initially considered to be a nonselective bulk degradation pathway, especially during stress such as starvation. However, given the critical role of mitochondria in myocytes, it seems unlikely that degradation of mitochondria is a random process, especially during energy deficient conditions such as starvation. This could lead to the degradation of too many mitochondria and compromise cellular survival. A recent study examined changes in the cellular proteome during starvation and found that cytosolic proteins, multiprotein complexes, and organelles show distinct patterns of degradation (46). This study reported that cytosolic proteins are degraded early during starvation, whereas mitochondria are degra...

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“…At the onset of diabetes, the tumor suppressor protein p53 accumulates in the cytosol of mouse b-cells and inhibits PARKIN-mediated mitophagy. Mice deficient in p53 have restored mitophagy and are resistant to b-cell loss induced by streptozotocin (STZ) (63). The PINK1/PARKIN pathway plays an important role in mitochondrial quality control in the heart (16,68,90).…”

Section: Mitochondrial Autophagymentioning

confidence: 99%

“…As a result, the removal of damaged mitochondria is abrogated and dysfunctional mitochondria accumulate, leading to cardiac functional decline (64). Inhibition of PARKIN-mediated mitophagy by p53 has also been linked to impaired function of pancreatic b-cells in T1D (63). However, whether cytosolic p53 contributes to the development of diabetic cardiomypathy by inhibiting PARKIN-mediated mitophagy in myocytes remains to be determined.…”

Section: Mitophagy and P53 In Diabetesmentioning

confidence: 99%

Unbreak My Heart: Targeting Mitochondrial Autophagy in Diabetic Cardiomyopathy

Kubli

Gustafsson

2015

Antioxidants & Redox Signaling

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Significance: Diabetes is strongly associated with increased incidence of heart disease and mortality due to development of diabetic cardiomyopathy. Even in the absence of cardiovascular disease, cardiomyopathy frequently arises in diabetic patients. Current treatment options for cardiomyopathy in diabetic patients are the same as for nondiabetic patients and do not address the causes underlying the loss of contractility. Recent Advances: Although there are numerous distinctions between Type 1 and Type 2 diabetes, recent evidence suggests that the two disease states converge on mitochondria as an epicenter for cardiomyocyte damage. Critical Issues: Accumulation of dysfunctional mitochondria contributes to cardiac tissue injury in both acute and chronic conditions. Removal of damaged mitochondria by macroautophagy, termed ''mitophagy,'' is critical for maintaining cardiomyocyte health and contractility both under normal conditions and during stress. However, very little is known about the involvement of mitophagy in the pathogenesis of diabetic cardiomyopathy. A growing interest in this topic has given rise to a wave of publications that aim at deciphering the status of autophagy and mitophagy in Type 1 and Type 2 diabetes. Future Directions: This review summarizes these recent studies with the goal of drawing conclusions about the activation or suppression of autophagy and mitophagy in the diabetic heart. A better understanding of how autophagy and mitophagy are affected in the diabetic myocardium is still needed, as well as whether they can be targeted therapeutically. Antioxid. Redox Signal. 22, 1527Signal. 22, -1544

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Inhibition of p53 preserves Parkin-mediated mitophagy and pancreatic β-cell function in diabetes

Cited by 190 publications

References 32 publications

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

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

Mending a broken heart: the role of mitophagy in cardioprotection

Unbreak My Heart: Targeting Mitochondrial Autophagy in Diabetic Cardiomyopathy

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