Mitochondrial effectors of cellular senescence: beyond the free radical theory of aging

Ziegler, Dorian V.; Wiley, Christopher D.; Velarde, Michael C.

doi:10.1111/acel.12287

Cited by 308 publications

(269 citation statements)

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“…Moreover, recent findings suggest the possibility of induction of SIPS independently of ROS generation (Ziegler et al, 2015). In the present study, we noted the increase of the% of the cells positive for the presence of SA-b-gal, which widely serves as a senescence marker (Fig.…”

Section: Independent Of Oxidative Stress-induced Premature Senescencesupporting

confidence: 76%

Cytotoxic and cytostatic side effects of chitosan nanoparticles as a non-viral gene carrier

Bor

Mytych

Żebrowski

et al. 2016

International Journal of Pharmaceutics

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Section: Independent Of Oxidative Stress-induced Premature Senescencesupporting

confidence: 76%

Cytotoxic and cytostatic side effects of chitosan nanoparticles as a non-viral gene carrier

Bor

Mytych

Żebrowski

et al. 2016

International Journal of Pharmaceutics

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“…Mitochondrial dysfunction can induce cellular senescence (19,35). We have shown that constitutive Sod2 deficiency causes the chronic presence of senescent keratinocytes in the epidermis (19).…”

Section: Significancementioning

confidence: 99%

Pleiotropic age-dependent effects of mitochondrial dysfunction on epidermal stem cells

Velarde

Demaria

Melov

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Tissue homeostasis declines with age partly because stem/progenitor cells fail to self-renew or differentiate. Because mitochondrial damage can accelerate aging, we tested the hypothesis that mitochondrial dysfunction impairs stem cell renewal or function. We developed a mouse model, Tg(KRT14-cre/Esr1) 20Efu/J × Sod2 tm1Smel , that generates mitochondrial oxidative stress in keratin 14-expressing epidermal stem/progenitor cells in a temporally controlled manner owing to deletion of Sod2, a nuclear gene that encodes the mitochondrial antioxidant enzyme superoxide dismutase 2 (Sod2). Epidermal Sod2 loss induced cellular senescence, which irreversibly arrested proliferation in a fraction of keratinocytes. Surprisingly, in young mice, Sod2 deficiency accelerated wound closure, increasing epidermal differentiation and reepithelialization, despite the reduced proliferation. In contrast, at older ages, Sod2 deficiency delayed wound closure and reduced epidermal thickness, accompanied by epidermal stem cell exhaustion. In young mice, Sod2 deficiency accelerated epidermal thinning in response to the tumor promoter 12-O-tetradecanoylphorbol-13-acetate, phenocopying the reduced regeneration of older Sod2-deficient skin. Our results show a surprising beneficial effect of mitochondrial dysfunction at young ages, provide a potential mechanism for the decline in epidermal regeneration at older ages, and identify a previously unidentified age-dependent role for mitochondria in skin quality and wound closure.

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“…At the cellular level, converging evidence indicates that mitochondrial dysfunction and cellular senescence are interlinked processes (Ziegler, Wiley, & Velarde, 2015). This is well‐illustrated by the finding that complete removal of mitochondria from senescent cells prevents several features of cellular senescence (Correia‐Melo et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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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Mitochondrial effectors of cellular senescence: beyond the free radical theory of aging

Cited by 308 publications

References 100 publications

Cytotoxic and cytostatic side effects of chitosan nanoparticles as a non-viral gene carrier

Cytotoxic and cytostatic side effects of chitosan nanoparticles as a non-viral gene carrier

Pleiotropic age-dependent effects of mitochondrial dysfunction on epidermal stem cells

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

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