Regulation of autophagy by ROS: physiology and pathology

Scherz-Shouval, Ruth; Elazar, Zvulun

doi:10.1016/j.tibs.2010.07.007

Cited by 1,087 publications

(834 citation statements)

References 102 publications

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“…Previously, we reported that FOXO‐deficient neural cells have elevated mitochondria content with increased superoxide suggesting accumulation of defective mitochondria (Yeo et al., 2013). We therefore tested whether the beneficial effect of rapamycin could be explained by restoration of mitophagy and consequential attenuation of ROS generation as previously discussed (Scherz‐Shouval & Elazar, 2011). Antioxidant N‐acetylcysteine (NAC) treatment of presymptomatic KO mice suppressed the age‐progressive axonal degeneration and reactive microglia lesions in the spinal cord to a similar degree as rapamycin treatment (Figure 6e,f).…”

Section: Resultsmentioning

confidence: 99%

FOXO protects against age‐progressive axonal degeneration

Hwang

Santo

et al. 2017

Aging Cell

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SummaryNeurodegeneration resulting in cognitive and motor impairment is an inevitable consequence of aging. Little is known about the genetic regulation of this process despite its overriding importance in normal aging. Here, we identify the Forkhead Box O (FOXO) transcription factor 1, 3, and 4 isoforms as a guardian of neuronal integrity by inhibiting age‐progressive axonal degeneration in mammals. FOXO expression progressively increased in aging human and mouse brains. The nervous system‐specific deletion of Foxo transcription factors in mice accelerates aging‐related axonal tract degeneration, which is followed by motor dysfunction. This accelerated neurodegeneration is accompanied by levels of white matter astrogliosis and microgliosis in middle‐aged Foxo knockout mice that are typically only observed in very old wild‐type mice and other aged mammals, including humans. Mechanistically, axonal degeneration in nerve‐specific Foxo knockout mice is associated with elevated mTORC1 activity and accompanying proteotoxic stress due to decreased Sestrin3 expression. Inhibition of mTORC1 by rapamycin treatment mimics FOXO action and prevented axonal degeneration in Foxo knockout mice with accelerated nervous system aging. Defining this central role for FOXO in neuroprotection during mammalian aging offers an invaluable window into the aging process itself.

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Section: Resultsmentioning

confidence: 99%

FOXO protects against age‐progressive axonal degeneration

Hwang

Santo

et al. 2017

Aging Cell

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“…Mitochondria are important regulators of autophagy and apoptosis. Exogenous ROS and cytokines such as TNFa, both of which are increased during IBD, promote cellular injury and autophagy via mitochondrial ROS generation [29,30,31]. We show here that PHB modulates autophagy in intestinal and colonic epithelial cells.…”

Section: Discussionmentioning

confidence: 60%

“…It is widely accepted that ROS produced as a by-product of respiration as well as exogenous ROS can induce autophagy via mitochondrial damage [27,28]. Mitochondria are the main source of ROS for regulation of autophagy [29]. In fact, exogenous ROS and the proinflammatory cytokine tumor necrosis factor a (TNFa), both of which are increased during IBD, promote cellular injury and autophagy via mitochondrial ROS generation [29,30,31].…”

Section: Introductionmentioning

confidence: 99%

“…Mitochondria are the main source of ROS for regulation of autophagy [29]. In fact, exogenous ROS and the proinflammatory cytokine tumor necrosis factor a (TNFa), both of which are increased during IBD, promote cellular injury and autophagy via mitochondrial ROS generation [29,30,31]. Defects in autophagy result in the accumulation of intracellular ROS and deformed mitochondria [14,32].…”

Section: Introductionmentioning

confidence: 99%

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320 Prohibitin 1 Modulates Mitochondrial Stress-Related Autophagy in Human Colonic Epithelial Cells

Kathiria¹,

Butcher²,

Feagins³

et al. 2012

Gastroenterology

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“…Recently, ROS were demonstrated to promote starvation-induced autophagy, antibacterial autophagy and autophagic cell death (Scherz-Shouval and Elazar 2007). There is now an accumulating consensus that ROS controls autophagy in multiple contexts and cell types (Scherz-Shouval and Elazar 2007, 2011). Moreover, changes in ROS and autophagy regulation contribute to cancer initiation and progression (Tang et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Rasfonin promotes autophagy and apoptosis via upregulation of reactive oxygen species (ROS)/JNK pathway

Sun

Che²,

Jiang

2016

Mycology

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Rasfonin is a fungal secondary metabolite demonstrating with antitumour effects. Reactive oxygen species (ROS) are formed as a natural by-product of the normal metabolism of oxygen and have important roles in cell signalling and homeostasis. Studies reported that many fungal secondary metabolites activated either autophagy or apoptosis through ROS generation. In former study, we revealed that rasfonin induced both autophagy and apoptosis, however, whether it promoted aforementioned processes via upregulation of ROS generation remains explored. In the current work, we demonstrated that rasfonin induced autophagy and apoptosis concomitant with a dramatically ROS production. N-Acetylcysteine (NAC), an often used ROS inhibitor, decreased both autophagic flux and caspase-dependent apoptosis by rasfonin. Flow cytometry analysis revealed NAC was able to reduce rasfonin-dependent apoptosis and necrosis. In methanethiosulfonate (MTS) assay, we observed that NAC significantly blocked rasfonin-induced cell viability loss. In addition, we found that rasfonin increased the phosphorylation of c-Jun NH2-terminal kinase (JNK), which was inhibited by NAC. SP600125, an inhibitor of JNK, reduced rasfonin-dependent autophagic flux and apoptosis. Moreover, we demonstrated that rasfonin inhibited the phosphorylation of both 4E-binding protein 1 (4E-BP1) and S6 kinase 1 (S6K1), two main substrates of mammalian target of rapamycin (mTOR). Collectively, rasfonin activated autophagy and apoptosis through upregulation of ROS/JNK signalling.

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Regulation of autophagy by ROS: physiology and pathology

Cited by 1,087 publications

References 102 publications

FOXO protects against age‐progressive axonal degeneration

FOXO protects against age‐progressive axonal degeneration

320 Prohibitin 1 Modulates Mitochondrial Stress-Related Autophagy in Human Colonic Epithelial Cells

Rasfonin promotes autophagy and apoptosis via upregulation of reactive oxygen species (ROS)/JNK pathway

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