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Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4
Open accessAbstract
Autophagy is a major catabolic pathway by which eukaryotic cells degrade and recycle macromolecules and organelles. This pathway is activated under environmental stress conditions, during development and in various pathological situations. In this study, we describe the role of reactive oxygen species (ROS) as signaling molecules in starvation-induced autophagy. We show that starvation stimulates formation of ROS, specifically H(2)O(2). These oxidative conditions are essential for autophagy, as treatment with antioxidative agents abolished the formation of autophagosomes and the consequent degradation of proteins. Furthermore, we identify the cysteine protease HsAtg4 as a direct target for oxidation by H(2)O(2), and specify a cysteine residue located near the HsAtg4 catalytic site as a critical for this regulation. Expression of this regulatory mutant prevented the formation of autophagosomes in cells, thus providing a molecular mechanism for redox regulation of the autophagic process.
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“Induction of autophagy following nutrient starvation requires the production of hydrogen peroxide that oxidizes autophagy‐related (ATG)4.”
From Reactive Oxygen Species in Cancer: Current Findings and Future Directions (2021) · cites this paper as [51]
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“MTOR suppression does not always induce autophagy, such as when BECN1 undergoes inhibitory phosphorylation by the growth factor signaling molecules EGFR and AKT, when microglia are activated by lipopolysaccharide (LPS), a TLR4 ligand [766], or during Salmonella infection [767-769].”
From Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition) 1 (2021) · cites this paper as [767]
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BackgroundHigh levels of Fis1, a pro-fission mitochondrial protein, trigger autophagy
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Does autophagy have a license to kill mammalian cells?
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“Indeed, during starvation mitochondrial ROS production is enhanced and autophagy increased (Scherz-Shouval et al., 2007).”
BackgroundScherz‐Shouval, R., Weidberg, H., Gonen, C., Wilder, S., Elazar, Z., & Oren, M. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1006124107 · Cited by 243
“2A, levels of mRNA encoding LC3B, one of the three human LC3 isoforms, did not change on very short starvation, as reported earlier (25).”
BackgroundSelf-citationKim, S. I., Na, H.-J., Ding, Y., Wang, Z., Lee, S., & Choi, M. E. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.308460 · Cited by 235
“Autophagy can be up-regulated in response to both external and intracellular factors, including amino acid starvation (12), growth factor withdrawal (13), low cellular energy levels (14), endoplasmic reticulum (ER) stress (15), hypoxia (16), oxidative stress (17), pathogen infection (18), and organelle damage (19).”
BackgroundAutophagy mediates an amplification loop during ferroptosis
Lee, S., Hwang, N., Seok, B. G., Lee, S., Lee, S., & Chung, S. W. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-05978-8 · Cited by 253
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Levonen, A., Hill, B. G., Kansanen, E., Zhang, J., & Darley-Usmar, V. M. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.03.025 · Cited by 235
“ATG4 is a cysteine protease important for cleavage of pro-LC3 to produce LC3-I, and delipidation of autophagosomal outer membrane LC3-II for recycling [61,62].”
BackgroundAssessing autophagy in the context of photodynamic therapy
Reiners, J. J., Agostinis, P., Berg, K., Oleinick, N. L., & Kessel, D. H. (2010) · Autophagy · doi:10.4161/auto.6.1.10220 · Cited by 237
Role of Oxidative Stress in Stem, Cancer, and Cancer Stem Cells
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Gottlieb, R. A., & Carreira, R. (2010) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00097.2010 · Cited by 230
“Autophagy is also induced by oxidative stress, and amino acid restriction has been shown to trigger production of reactive oxygen species (ROS).”
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Huang, J., Lam, G. Y., & Brumell, J. H. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3554 · Cited by 228
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BackgroundInvolvement of Autophagy in Oncogenic K-Ras-induced Malignant Cell Transformation
Kim, M. J., Woo, S.-J., Yoon, C., Lee, J., An, S., Choi, Y. H., Hwang, S., Yoon, G., & Lee, S. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.138958 · Cited by 239
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Mitophagy and Parkinson's disease: The PINK1–parkin link
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“LC3-I, which resides in the cytoplasm, is converted to LC3-II through two-ubiquitin like modifications, which covalently link the protein to phosphatidylethanolamine (PE) [24].”
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“67,68 Notably, SiNPs exposure affected autophagy of endothelial cells in two ways, including the induction of autophagosome synthesis via increasing LC3-II expression, and reduction of autophagosome degradation as shown by the lysosome impairment and p62 accumulation.”
Contribution of Impaired Mitochondrial Autophagy to Cardiac Aging
Dutta, D., Calvani, R., Bernabei, R., Leeuwenburgh, C., & Marzetti, E. (2012) · Circulation Research · doi:10.1161/circresaha.111.246108 · Cited by 224
Autophagy and mitophagy in cellular damage control
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“On the other hand, Atg4 is activated in reduced conditions, and inactivated in response to oxidative stress [39].”
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Deretic, V. P., Jiang, S., & Dupont, N. (2012) · Trends in Cell Biology · doi:10.1016/j.tcb.2012.04.008 · Cited by 224
“ROS, through a redox-sensitive Cys residue in Atg4 (Cys81 in ATG4A and Cys78 in ATG4B), inactivate this protease [34] that otherwise reverses Atg8-PE modification required for autophagic membrane growth [33] and closure [32], with ROS thus favoring autophagosome expansion (Figure 1, model 2).”
BackgroundPuyal, J., Ginet, V., & Clarke, P. G. H. (2013) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2013.03.002 · Cited by 224
“, 2008), hypoxia (Scherz-Shouval and Elazar, 2007) and reactive oxygen species (H2O2 and O2) production (Chen et al., 2009; He and Klionsky, 2009; Scherz-Shouval et al., 2007).”
BackgroundZinc oxide nanoparticles induce apoptosis by enhancement of autophagy via PI3K/Akt/mTOR inhibition
Roy, R., Singh, S. K., Chauhan, L. K. S., Das, M., Tripathi, A., & Dwivedi, P. D. (2014) · Toxicology Letters · doi:10.1016/j.toxlet.2014.02.024 · Cited by 222
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“For example, hydrogen peroxide directly facilitates formation of the autophagosome by oxidizing Atg4 (Scherz-Shouval et al. 2007).”
BackgroundAutophagy and its role in plant abiotic stress management
Avin‐Wittenberg, T. (2018) · Plant Cell & Environment · doi:10.1111/pce.13404 · Cited by 214
Outstanding Questions in Mitophagy: What We Do and Do Not Know
Montava‐Garriga, L., & Ganley, I. G. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.06.032 · Cited by 218
“Amino acid starvation was reported to increase reactive oxygen species (ROS) co-localising with mitochondria, suggesting a potential correlation with increased mitochondria activity or dysfunction [80,81].”
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“Autophagy is the process in which cytoplasmic contents within a cell are sequestered within a doublemembraned vacuole that subsequently fuses with lysosomes, resulting in degradation of the contents.(33)”
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Eisenberg‐Lerner, A., & Kimchi, A. (2009) · APOPTOSIS · doi:10.1007/s10495-008-0307-5 · Cited by 220
“Examples of these include etoposide, an inducer of p53-dependent apoptosis, that was shown to induce autophagy in mouse embryonic fibroblasts in a p53-dependent manner [89]; Ligation of the TRAIL receptor-2 by human scFv antibody triggered autophagic cell death in both TRAIL-sensitive and TRAILresistant cancer cells […”
BackgroundReactive Oxygen Species in Photodynamic Therapy: Mechanisms of Their Generation and Potentiation
Dąbrowski, J. M. (2017) · Advances in inorganic chemistry · doi:10.1016/bs.adioch.2017.03.002 · Cited by 223
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“…as H2O2, as well as ROS inducers, including MV, can induce autophagy in mammalian cells and Arabidopsis plants (Kunchithapautham and Rohrer, 2007; Scherz-Shouval et al., 2007; (A) to (C) Silencing of Nb-GAPCs (GAPCs-VIGS) enhanced N gene-mediated resistance against TMV. (A) Representative…”
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“starvation conditions, as H2O2 release by mitochondria appears to play an important role in the induction of autophagosome formation [27].”
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The Role of Autophagy in Cancer
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“…under stress conditions, such as hypoxia or nutrient deprivation, autophagy is a prosurvival mechanism that eliminates unfolded proteins and provides substrates for adenosine triphosphate (ATP) production by rapidly degrading endogenous substrates (Figure 2) (Kuma et al. 2004, Singh & Cuervo 2011).”
BackgroundOxidative Stress Induces Parallel Autophagy and Mitochondria Dysfunction in Human Glioma U251 Cells
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“, H2O2) are generated at the levels of high enough to induce oxidation and damage to DNA, lipids, proteins, and other macromolecules (Matsui et al., 2007; Pelicano et al., 2004; Scherz-Shouval et al., 2007).”
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Autophagy: The Last Defense against Cellular Nutritional Stress
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“One study revealed that ROS accumulation is an essential element of autophagy induced by nutrient deficiency or rapamycin treatment (75).”
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“OS can render Atg4 inactive by oxidizing residue cysteine-81, thereby promoting lipidation of LC3-I, which is conducive to autophagy [57].”
BackgroundAge-related changes in skeletal muscle: changes to life-style as a therapy
McCormick, R., & Vasilaki, A. (2018) · Biogerontology · doi:10.1007/s10522-018-9775-3 · Cited by 227
Organelle-Specific Initiation of Autophagy
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“On the other hand, PEX14 interacts with lipidated LC3 via microtubules, further facilitating the recruitment of forming autophagosomes to peroxisomes destined to degradation (Hara-Kuge and Fujiki, 2008).”
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“Importantly, we also determined whether other forms of stress caused by exposure to anticancer agents such as etoposide or doxorubicin, or exposure to heat shock, UV light, or reactive oxygen species (ROS), which are well known to induce autophagy (2, 19, 32), also trigger acetylation of hsp70 and KAP1-dependent SUMOy…”
BackgroundOxidation of Atg3 and Atg7 mediates inhibition of autophagy
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“Studies have suggested that mTOR and PI3K activities mediate some of the autophagy response to oxidative stress (5;14;16;17;70-72), although it is also highly conceivable that modification of autophagy proteins at cysteine resides may also play a role in modulating autophagy.”
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“Accumulated evidence suggests that ROS can induce autophagy through several distinct mechanisms such as autophagy-related gene 4 (ATG4), protein kinase B (Akt)/mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK)/high mobility group box 1, and mitochondrial electron transport chain (6, 7, 50,…”
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“The excessive ROS production has been suggested to have a role in the initiation of autophagy.(26) Hence, the anti-oxidative effect of NAC on propionate-mediated autophagy was examined.”
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“Redox modifications of cysteine residues in ATG4 prevent delipidation of LC3, thereby promoting sustained autophagy.(96) In human adenocarcinoma cells, oxidative stress led to upregulation of ATG4 together with increased autophagy and increased invasion of cells through a Matrigel matrix.”
BackgroundMitochondrial Dynamics, ROS, and Cell Signaling: A Blended Overview
Brillo, V., Chieregato, L., Leanza, L., Muccioli, S., & Costa, R. (2021) · Life · doi:10.3390/life11040332 · Cited by 208
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BackgroundEndocytosis and Autophagy: Exploitation or Cooperation?
Tooze, S. A., Abada, A., & Elazar, Z. (2014) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a018358 · Cited by 202
“In mammals, this step is subjected to regulation by reactive oxygen species (ROS) formed by the mitochondria (Scherz-Shouval et al. 2007).”
BackgroundSelf-citationCurrent concepts on the role of inflammation in COPD and lung cancer
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“The mechanism underlying these observations is not known but it may be associated with increased oxidative stress in response to cigarette smoke since reactive oxygen species are known to induce autophagy [37].”
BackgroundRauf, A., Khalil, A. A., Awadallah, S. M., Khan, S. A., Abu‐Izneid, T., Kamran, M., Hemeg, H. A., Mubarak, M. S., Khalid, A., & Wilairatana, P. (2023) · Food Science & Nutrition · doi:10.1002/fsn3.3784 · Cited by 220
Mechanistic Links Between Oxidative Stress and Disuse Muscle Atrophy
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“, Beclin-1 and cathepsin L) in nonmuscle cell lines (4, 57, 69) (Fig.”
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Meijer, A. J., & Codogno, P. (2009) · Critical Reviews in Clinical Laboratory Sciences · doi:10.1080/10408360903044068 · Cited by 215
Redox implications of AMPK-mediated signal transduction beyond energetic clues
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“Nonetheless, protease autophagy-related gene 4 (Atg4) remains the sole example of an autophagic protein whose redox regulation has been demonstrated to be necessary for the progression of autophagy (Scherz-Shouval et al., 2007).”
BackgroundQiao, S., Dennis, M. J., Song, X., Vadysirisack, D. D., Salunke, D., Nash, Z. M., Yang, Z., Liesa, M., Yoshioka, J., Matsuzawa, S., et al. (2015) · Nature Communications · doi:10.1038/ncomms8014 · Cited by 199
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“In skeletal muscle, ROS/RNS have been identified as playing key roles in numerous physiological processes, including glucose uptake (163), excitation/contraction coupling (261), mitochondrial biogenesis (145), training adaptations (122, 281), and cell death (295).”
Impaired autophagy: A mechanism of mitochondrial dysfunction in anoxic rat hepatocytes
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“Intracellular ROS levels increase in response to energy deprivation.(17,18) However, exactly where and how ROS are produced and how ROS affect autophagy and survival of cardiomyocytes during energy deprivation remains to be elucidated.”
BackgroundProteostasis Failure in Neurodegenerative Diseases: Focus on Oxidative Stress
Höhn, A., Tramutola, A., & Cascella, R. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/5497046 · Cited by 208
“For this, cysteine protease Atg-4 inactivation is made with ROS accumulation in the cell, resulting in Atg-4 phosphoethanolamine precursor accumulation, which is also necessary for the beginning of autophagosome [258].”
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Photodynamic Therapy and Immunity: An Update
Falk‐Mahapatra, R., & Gollnick, S. O. (2020) · Photochemistry and Photobiology · doi:10.1111/php.13253 · Cited by 201
“Generation of ROS during PDT is a powerful trigger for formation of autophagosomes (22,24,30).”
BackgroundProtective Role of Autophagy in Palmitate-Induced INS-1 β-Cell Death
Choi, S., Lee, S.-M., Lee, Y.-J., Li, L.-J., Lee, S., Lee, J., Kim, Y., Jun, H., Lee, K. W., & KANG, Y. Y. (2008) · Endocrinology · doi:10.1210/en.2008-0483 · Cited by 197
“Because FFA has generated ROS in -cells and the antioxidants have prevented FFA-induced -cell dysfunction (36, 37), oxidative stress could be a mediator in the induction of FFA-induced autophagy activation in -cells (38).”
Autophagy in Neuroprotection and Neurodegeneration: A Question of Balance
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“Mitochondrial signals to trigger autophagy likely include oxidative alterations, kinase signals or depolarization [10,100–103].”
BackgroundUnder the ROS: Thiol network is the principal suspect for autophagy commitment
Filomeni, G., Desideri, E., Cardaci, S., Rotilio, G., & Ciriolo, M. R. (2010) · Autophagy · doi:10.4161/auto.6.7.12754 · Cited by 197
“On the basis of these observations, the question spontaneously arising is: “Are there proteins able to sense redox unbalance and regulate the autophagic process accordingly?” Despite the wide number of proteins functionally modulated by reversible oxidation of reactive cysteine(s), the protease Atg4 remains the sole e…”
BackgroundLoss of hepatic chaperone‐mediated autophagy accelerates proteostasis failure in aging
Schneider, J. L., Villarroya, J., Díaz-Carretero, A. M., Patel, B., Urbanska, A. M., Thi, M. M., Villarroya, F., Santambrogio, L., & Cuervo, A. M. (2015) · Aging Cell · doi:10.1111/acel.12310 · Cited by 201
“Although both macroautophagy (Scherz-Shouval et al., 2007) and CMA (Kiffin et al.”
BackgroundInteractions between reactive oxygen species and autophagy
Redza-Dutordoir, M., & Averill‐Bates, D. A. (2021) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2021.119041 · Cited by 199
Autophagy-regulating protease Atg4: structure, function, regulation and inhibition
Maruyama, T., & Noda, N. N. (2018) · The Journal of Antibiotics · doi:10.1038/ja.2017.104 · Cited by 190
Sex differences in mitochondrial (dys)function: Implications for neuroprotection
Demarest, T. G., & McCarthy, M. M. (2015) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-014-9583-7 · Cited by 192
“Indeed, oxidative stress is sufficient to induce autophagy/mitophagy ((Scherz-Shouval et al. 2007) as cited by (Au et al. 2010)) and is necessary for the normal progression of autophagic recycling ((Zhu et al. 2007) as cited by (Au et al. 2010)).”
Mitophagy Is Required for Acute Cardioprotection by Simvastatin
Andres, A. M., Hernandez, G., Lee, P., Huang, C., Ratliff, E. P., Sin, J., Thornton, C. A., Damasco, M. V., & Gottlieb, R. A. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2013.5416 · Cited by 189
“Localized ROS prevents Atg4-mediated cleavage of CoQ from internal membranes, thus facilitating formation of autophagosomes at the site of ROS-generating structures (such as mitochondria) (51).”
Regulation of autophagy by amino acids and MTOR-dependent signal transduction
Meijer, A. J., Lorin, S., Blommaart, E. F. C., & Codogno, P. (2014) · Amino Acids · doi:10.1007/s00726-014-1765-4 · Cited by 203
“, in starvation) activates autophagy as a protective mechanism, and this occurs in a manner that is sensitive to antioxidants (Scherz-Shouval et al. 2007; Li et al. 2012a; Morales et al. 2014; Rahman et al. 2014) which, simultaneously, stimulate MTOR activity (Li et al.”
BackgroundMechanisms of mitochondria and autophagy crosstalk
Rambold, A. S., & Lippincott‐Schwartz, J. (2011) · Cell Cycle · doi:10.4161/cc.10.23.18384 · Cited by 200
Liver autophagy: much more than just taking out the trash
Schneider, J. L., & Cuervo, A. M. (2013) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2013.211 · Cited by 198
Oxidation of SQSTM1/p62 mediates the link between redox state and protein homeostasis
Carroll, B., Otten, E. G., Manni, D., Stefanatos, R. K. A., Menzies, F. M., Smith, G. R., Jurk, D., Kenneth, N. S., Wilkinson, S., Passos, J. F., et al. (2018) · Nature Communications · doi:10.1038/s41467-017-02746-z · Cited by 195
Autophagy in tumour suppression and promotion
Brech, A., Ahlquist, T. C., Lothe, R. A., & Stenmark, H. (2009) · Molecular Oncology · doi:10.1016/j.molonc.2009.05.007 · Cited by 194
“An interesting candidate in this context is ATG4C, a protease that mediates autophagosome formation (Scherz-Shouval et al., 2007) through processing of LC3/ATG8.”
BackgroundChen, M., Wang, Y., Deng, S., Lian, Z., & Yu, K. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.964130 · Cited by 187
“Specifically, elevated ROS levels cause oxidation of DNA, proteins, and lipids; increased protein carbonylation; impaired myogenic proteins and autophagy process; and inhibited skeletal muscle cell differentiation (Scherz-Shouval et al., 2007; Sandiford et al., 2014; Sakellariou et al., 2016).”
BackgroundMatsui, Y., Kyoi, S., Takagi, H., Hsu, C.-P., Hariharan, N., Ago, T., Vatner, S. F., & Sadoshima, J. (2008) · Autophagy · doi:10.4161/auto.5638 · Cited by 188
Copper Oxide Nanoparticles Induce Autophagic Cell Death in A549 Cells
Sun, T., Yan, Y., Zhao, Y., Guo, F., & Jiang, C. (2012) · PLoS ONE · doi:10.1371/journal.pone.0043442 · Cited by 189
The interplay between autophagy and ROS in tumorigenesis
Kongara, S., & Karantza, V. (2012) · Frontiers in Oncology · doi:10.3389/fonc.2012.00171 · Cited by 186
“CROSSTALK BETWEEN ROS AND AUTOPHAGY: ROS MODULATE AUTOPHAGY AUTOPHAGY INDUCTION IN RESPONSE TO ROS Direct effect on Atg proteins Amino acid deprivation induces the formation of H2O2 in mitochondria in a Class III PI3K-dependent manner, and this ROS is essential for the induction of autophagy in response to starvation…”
BackgroundIs Autophagy in Response to Ischemia and Reperfusion Protective or Detrimental for the Heart?
Sciarretta, S., Hariharan, N., Monden, Y., Zablocki, D., & Sadoshima, J. (2010) · Pediatric Cardiology · doi:10.1007/s00246-010-9855-x · Cited by 187
“Findings show that ROS oxidize and inhibits the cysteine protease activity of Atg4, which results in LC3 lipidation and autophagy [27].”
Wang, X., Wang, X.-L., Chen, H., Wu, D., Chen, J., Wang, X., Li, R., He, J., Mo, L., Cen, X., et al. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2014.01.040 · Cited by 183
Mehta, S. L., Kumari, S., Mendelev, N., & Li, P. A. (2012) · BMC Neuroscience · doi:10.1186/1471-2202-13-79 · Cited by 184
“It has been reported that ROS is a major factor involved in activation of autophagy [46,47] and selenium lowers ROS production and prevents mitochondrial dysfunction [34,48].”
BackgroundMammalian macroautophagy at a glance
Ravikumar, B., Futter, M., Jahreiss, L., Korolchuk, V. I., Lichtenberg, M., Luo, S., Massey, D. C. O., Menzies, F. M., Narayanan, U., Renna, M., et al. (2009) · Journal of Cell Science · doi:10.1242/jcs.031773 · Cited by 196
Mitochondria regulate autophagy by conserved signalling pathways
Graef, M., & Nunnari, J. M. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.104 · Cited by 183
“Inhibition of respiratory complexes has been associated with an increased generation of reactive oxygen species, previously implicated in mammalian autophagy regulation (Scherz-Shouval et al, 2007; Lambert and Brand, 2009).”
BackgroundReactive oxygen species (ROS) are a key determinant of cancer's metabolic phenotype
Rodic, S., & Vincent, M. D. (2017) · International Journal of Cancer · doi:10.1002/ijc.31069 · Cited by 186
“Through recycling organelles including the mitochondria, autophagy reduces cellular metabolism and thereby limits ROS production.(113,114) The second phenotype we propose involves a high level of glycolysis which may be more viable for proliferating cells when glucose is abundant.”
BackgroundDrug Resistance in Glioblastoma: The Two Faces of Oxidative Stress
Olivier, C., Oliver, L., Lalier-Bretaudeau, L., & Vallette, F. M. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2020.620677 · Cited by 191
Small molecules regulating reactive oxygen species homeostasis for cancer therapy
Zhang, J., Duan, D., Song, Z., Liu, T., Hou, Y., & Fang, J. (2021) · Medicinal Research Reviews · doi:10.1002/med.21734 · Cited by 184
“In addition, ROS can downregulate another ATG protein ATG4 expression by oxidizing its catalytic cysteine residues, leading to the increased autophagy.(109) In general, it is worth noting that ROS regulation of autophagy is dependent on the context determined by the type, intensity,”
BackgroundOxidation as a Post-Translational Modification that Regulates Autophagy
Scherz‐Shouval, R., Shvets, E., & Elazar, Z. (2007) · Autophagy · doi:10.4161/auto.4214 · Cited by 182
Self-citationWang, Q., Liang, B., Shirwany, N. A., & Zou, M. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017234 · Cited by 187
“[16] recently reported that ROS are essential for autophagy and specifically regulate the activity of Atg4.”
BackgroundIL-21 and T follicular helper cells
Spolski, R. J., & Leonard, W. J. (2009) · International Immunology · doi:10.1093/intimm/dxp112 · Cited by 192
Unsaturated lipid peroxidation-derived aldehydes activate autophagy in vascular smooth-muscle cells
Hill, B. G., Haberzettl, P., Ahmed, Y., Srivastava, S., & Bhatnagar, A. (2008) · Biochemical Journal · doi:10.1042/bj20071063 · Cited by 187
Oxidative stress-induced autophagy in plants: The role of mitochondria
Minibayeva, F. V., Dmitrieva, S. А., Ponomareva, A. A., & Ryabovol, V. (2012) · Plant Physiology and Biochemistry · doi:10.1016/j.plaphy.2012.02.013 · Cited by 499
“It promotes survival by degrading proteins and organelles damaged during oxidative stress, but it is also activated as a part of death programs, when the damage cannot be overcome [25].”
BackgroundInfluentialThe Role of Oxidative Stress, Mitochondrial Function, and Autophagy in Diabetic Polyneuropathy
Sifuentes-Franco, S., Pacheco-Moisés, F. P., Rodríguez-Carrizález, A. D., & Miranda‐Díaz, A. G. (2017) · Journal of Diabetes Research · doi:10.1155/2017/1673081 · Cited by 186
“The increase in ROS is essential for autophagy to prosper because in the presence of ROS it is possible to control the Atg4 activity, a family of cysteine proteases that are necessary for the formation of autophagosomes [98].”
BackgroundZhang, S., Hu, L., Jiang, J., Li, H., Wu, Q. J., Ooi, K., Wang, J., Feng, Y., Zhu, D., & Xia, C. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1673-3 · Cited by 180
Deconvoluting the role of reactive oxygen species and autophagy in human diseases
Wen, X., Wu, J., Wang, F., Liu, B., Huang, C., & Wei, Y. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.07.013 · Cited by 181
Cancer drug resistance: redox resetting renders a way
Liu, Y., Li, Q., Zhou, L., Xie, N., Nice, E. C., Zhang, H., Huang, C., & Lei, Y. (2016) · Oncotarget · doi:10.18632/oncotarget.8600 · Cited by 182
“The activity of Atg4, which has been shown to be involved in the processing of LC3, has also been proved to be sensitive to H2O2 [113].”
BackgroundInfluentialSimonaro, C. M., Ge, Y., Eliyahu, E., He, X., Jepsen, K. J., & Schuchman, E. H. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0912937107 · Cited by 176
“Autophagy is an important normal function of the lysosomal/endosomal system and has been shown to protect cells from inflammation caused by oxidative stress (18).”
Backgroundp62 at the Interface of Autophagy, Oxidative Stress Signaling, and Cancer
Nezis, I. P., & Stenmark, H. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4394 · Cited by 186
All-you-can-eat: autophagy in neurodegeneration and neuroprotection
Jaeger, P. A., & Wyss‐Coray, T. (2009) · Molecular Neurodegeneration · doi:10.1186/1750-1326-4-16 · Cited by 181
Metadata
- Authors
- Scherz‐Shouval, R., Shvets, E., Fass, E., Shorer, H., Gil, L., & Elazar, Z.
- Affiliations
- Weizmann Institute of Science (IL)
- Corresponding author
- Elazar, Zvulun
- Venue
- The EMBO Journal
- Published
- 2007-03-08
- Volume
- 26
- Issue
- 7
- Pages
- 1749-1760
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC6517991
- OpenAlex
- W2114806766
- Cited by
- 2,101
- References
- 51
- Citations by year
- 2026: 38 · 2025: 60 · 2024: 77 · 2023: 86 · 2022: 115 · 2021: 141 · 2020: 137 · 2019: 108 · 2018: 122 · 2017: 136 · 2016: 118 · 2015: 132 · 2014: 170 · 2013: 140 · 2012: 146
- FWCI
- 59.86
- Type
- journal article
- Language
- en
- Update notices
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Israel Science Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- reactive oxygen species, autophagy, ATG4, hydrogen peroxide, starvation, redox regulation, cysteine protease, autophagosome formation, oxidative stress signaling, protein degradation
- MeSH terms
- Autophagy-Related Proteins, Amino Acid Sequence, Animals, Autophagy, Cricetulus, Cysteine, Cysteine Endopeptidases, Enzyme Activation, Food Deprivation, Cricetinae, HeLa Cells, Humans, Models, Biological, Molecular Sequence Data, Mutation, Oxidation-Reduction, Phylogeny, CHO Cells, Reactive Oxygen Species, Phosphatidylinositol 3-Kinases, Mice
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