Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4

Scherz-Shouval, Ruth; Shvets, Elena; Fass, Ephraim; Shorer, Hagai; Gil, Lidor; Elazar, Zvulun

doi:10.1038/sj.emboj.7601623

Cited by 1,829 publications

(1,553 citation statements)

References 51 publications

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“…Furthermore, it has recently been shown that oxygen radicals are essential for starvation-induced autophagy in vitro (Scherz-Shouval et al, 2007). For these reasons, we tested the antioxidant GCEE for its capacity to reduce oxidative stress and evidence of autophagosomal vacuole formation.…”

Section: Discussionmentioning

confidence: 99%

Autophagy is Increased after Traumatic Brain Injury in Mice and is Partially Inhibited by the Antioxidant γ-glutamylcysteinyl Ethyl Ester

Lai

Chen

et al. 2007

J Cereb Blood Flow Metab

156

112

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Autophagy is a homeostatic process for recycling of proteins and organelles, induced by nutrient deprivation and regulated by oxygen radicals. Whether autophagy is induced after traumatic brain injury (TBI) is not established. We show that TBI in mice results in increased ultrastructural and biochemical evidence of autophagy. Specifically, autophagosomal vacuoles and secondary lysosomes were frequently observed in cell processes and axons in ipsilateral brain regions by electron microscopy, and lipidated microtubule-associated protein light chain 3, a biochemical footprint of autophagy referred to as LC3 II, was increased at 2 and 24 h after TBI versus controls. Since oxygen radicals are believed to be important in the pathogenesis of TBI and are essential for the process of starvation-induced autophagy in vitro, we also sought to determine if treatment with the antioxidant c-glutamylcysteinyl ethyl ester (GCEE) reduced autophagy and influenced neurologic outcome after TBI in mice. Treatment with GCEE reduced oxidative stress and partially reduced LC3 II formation in injured brain at 24 h after TBI versus vehicle. Treatment with GCEE also led to partial improvement in behavioral and histologic outcome versus vehicle. Taken together, these data show that autophagy occurs after experimental TBI, and that oxidative stress contributes to overall neuropathology, in part by initiating or influencing autophagy.

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Section: Discussionmentioning

confidence: 99%

Autophagy is Increased after Traumatic Brain Injury in Mice and is Partially Inhibited by the Antioxidant γ-glutamylcysteinyl Ethyl Ester

Lai

Chen

et al. 2007

J Cereb Blood Flow Metab

156

112

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“…Recent evidence suggests the involvement of ROS in autophagy [24]. To determine if autophagy is increased in MERRF fibroblasts, first we analyzed the expression of the genes ATG12, BECLIN1, and LC3, which encode proteins involved in autophagy.…”

Section: Mitochondrial Degradation In Merrf Fibroblastsmentioning

confidence: 99%

Recovery of MERRF Fibroblasts and Cybrids Pathophysiology by Coenzyme Q10

et al. 2012

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Mitochondrial DNA mutations are an important cause of human disease for which there is no effective treatment. Myoclonic epilepsy with ragged-red fibers (MERRF) is a mitochondrial disease usually caused by point mutations in transfer RNA genes encoded by mitochondrial DNA. The most common mutation associated with MERRF syndrome, m.8344A>G in the gene MT-TK, which encodes transfer RNA Lysine , affects the translation of all mitochondrial DNA encoded proteins. This impairs the assembly of the electron transport chain complexes leading to decreased mitochondrial respiratory function. Here we report on how this mutation affects mitochondrial function in primary fibroblast cultures established from patients harboring the A8344G mutation. Coenzyme Q 10 (CoQ) levels, as well as mitochondrial respiratory chain activity, and mitochondrial protein expression levels were significantly decreased in MERRF fibroblasts. Mitotracker staining and imaging analysis of individual mitochondria indicated the presence of small, rounded, depolarized mitochondria in MERRF fibroblasts. Mitochondrial dysfunction was associated with increased oxidative stress and increased degradation of impaired mitochondria by mitophagy. Transmitochondrial cybrids harboring the A8344G mutation also showed CoQ deficiency, mitochondrial dysfunction, and increased mitophagy activity. All these abnormalities in patient-derived fibroblasts and cybrids were partially restored by CoQ supplementation, indicating that these cell culture models may be suitable for screening and validation of novel drug candidates for MERRF disease.

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“…Oxidative stress has been implicated in the induction of degradative autophagy [51]. It has been reported that oxidation of Atg4 at cysteine inactivates its delipidating activity on LC3, thereby leading to the induction of autophagosome formation [52]. It has also been proposed that AMPK may be activated in response to increased intracellular ROS levels, particularly through S-glutathionylation [53].…”

Section: Discussionmentioning

confidence: 99%

6-Hydroxydopamine induces secretion of PARK7/DJ-1 via autophagy-based unconventional secretory pathway

et al. 2018

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PARK7/DJ-1 is a Parkinson disease- and cancer-associated protein that functions as a multifunctional protein involved in gene transcription regulation and anti-oxidative defense. Although PARK7 lacks the secretory signal sequence, it is secreted and plays important physiological and pathophysiological roles. Whereas secretory proteins that lack the endoplasmic reticulum-targeting signal sequence are secreted from cells by way of what is called the unconventional secretion mechanism, the specific processes responsible for causing PARK7 to be secreted across the plasma membrane have remained unclear. In the present study, we found that PARK7 secretion was increased by treatment with 6-OHDA via the unconventional secretory pathway in human neuroblastoma SH-SY5Y cells and MEF cells. We also found that 6-OHDA-induced PARK7 secretion was suppressed in Atg5-, Atg9-, or Atg16l1-deficient MEF cells or ATG16L1 knockdown SH-SY5Y cells, indicating that the autophagy-based unconventional secretory pathway is involved in PARK7 secretion. We moreover observed that 6-OHDA-derived electrophilic quinone induced oxidative stress as indicated by a decrease in glutathione levels, and that this was suppressed by pretreatment with antioxidant NAC. We further found that NAC treatment suppressed autophagy and PARK7 secretion. We also observed that 6-OHDA-induced autophagy was associated with activation of AMPK and ULK1 via a pathway which was independent of MTOR. Collectively these results suggest that electrophilic 6-OHDA quinone enhances oxidative stress, and that this is followed by AMPK-ULK1 pathway activation and induction of secretory autophagy to produce unconventional secretion of PARK7.Abbreviations: 6-OHDA: 6-hydroxydopamine; AMPK: AMP-activated protein kinase; ATG: autophagy related; CAV1: caveolin 1; ER: endoplasmic reticulum; FN1: fibronectin 1; GSH: glutathione; IDE: insulin degrading enzyme; IL: interleukin; LDH: lactate dehydrogenase; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MEF: mouse embryonic fibroblast; MTOR: mechanistic target of rapamycin kinase; NAC: N-acetyl-L-cysteine; PARK7/DJ-1: Parkinsonism associated deglycase; PD: Parkinson disease; RPS6KB1/p70S6K: ribosomal protein S6 kinase B1; RPN1: ribophorin I; ROS: reactive oxygen species; ULK1: unc-51 like autophagy activating kinase 1; WT: wild-type

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Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4

Cited by 1,829 publications

References 51 publications

Autophagy is Increased after Traumatic Brain Injury in Mice and is Partially Inhibited by the Antioxidant γ-glutamylcysteinyl Ethyl Ester

Autophagy is Increased after Traumatic Brain Injury in Mice and is Partially Inhibited by the Antioxidant γ-glutamylcysteinyl Ethyl Ester

Recovery of MERRF Fibroblasts and Cybrids Pathophysiology by Coenzyme Q10

6-Hydroxydopamine induces secretion of PARK7/DJ-1 via autophagy-based unconventional secretory pathway

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