Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L, Elazar ZReactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J 26:1749-1760

Department of Biological Chemistry, The Weizmann Institute of Science, 76100 Rehovot, Israel.
The EMBO Journal (Impact Factor: 10.43). 05/2007; 26(7):1749-60. DOI: 10.1038/sj.emboj.7601623
Source: PubMed


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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Available from: Elena Shvets, Feb 06, 2015
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    • "ROS, especially mitochondrial ROS, serve as signaling molecules in inducing autophagy [69]. Atg4, a cysteine protease which cleaves Atg8/LC3 from the outer membrane of autophagosome, is targeted and inactivated by ROS, leading to the lipidation of autophagic process [70]. At the same time, autophagy contributes to the regulation of cellular ROS production by eliminating damaged organelles that may produce high levels of ROS which, in turn, limits chromosomal instability [71]. "
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    ABSTRACT: Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · Nov 2015 · Seminars in Cancer Biology
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    • "Depolarization of mitochondria is a prerequisite for Parkin-dependent mitophagy, but mitophagy mediated by Bnip3 and NIX may be triggered through other pathways including reactive oxygen species (ROS) [15], which promote dimerization of Bnip3 (and potentially NIX) on the mitochondrial outer membrane [16]. Nutrient stress (fasting) activates AMPK and general autophagy, which is associated with production of ROS from mitochondrial complex I [17]; however, fasting-induced mitophagy is impaired in cyclophilin D-deficient mice [18], which have hyperpolarized mitochondria. Thus there are hints that mitophagy initiated by nutrient stress may be initiated by mitochondrial depolarization and Parkin translocation, but a role for ROS and Bnip3 is not excluded. "
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    ABSTRACT: Balancing mitophagy and mitochondrial biogenesis is essential for maintaining a healthy population of mitochondria and cellular homeostasis. Coordinated interplay between these two forces that govern mitochondrial turnover plays an important role as an adaptive response against various cellular stresses that can compromise cell survival. Failure to maintain the critical balance between mitophagy and mitochondrial biogenesis or homeostatic turnover of mitochondria results in a population of dysfunctional mitochondria that contribute to various disease processes. In this review we outline the mechanics and relationships between mitophagy and mitochondrial biogenesis, and discuss the implications of a disrupted balance between these two forces, with an emphasis on cardiac physiology. This article is part of a Special Issue entitled 'Mitochondria'. Copyright © 2014. Published by Elsevier Ltd.
    Full-text · Article · Oct 2014 · Journal of Molecular and Cellular Cardiology
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    • "The basal physiological levels of ROS act as intracellular signaling molecules that mediate cellular responses to nutrient deprivation, hypoxia, and others [18]. Recent data show that ROS regulates both death-related autophagy and starvation-induced autophagy for cell survival [19,20,21]. It has been shown that autophagy-defective cells accumulate damaged mitochondria and exhibit increased production of ROS [22,23], suggesting that autophagy serves to reduce the damage done by excessive ROS production [20,24]. "
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    ABSTRACT: Objective Under estrogen deficiency, blastocysts cannot initiate implantation and enter dormancy. Dormant blastocysts live longer in utero than normal blastocysts, and autophagy has been suggested as a mechanism underlying the sustained survival of dormant blastocysts during delayed implantation. Autophagy is a cellular degradation pathway and a central component of the integrated stress response. Reactive oxygen species (ROS) are produced within cells during normal metabolism, but their levels increase dramatically under stressful conditions. We investigated whether heightened autophagy in dormant blastocysts is associated with the increased oxidative stress under the unfavorable condition of delayed implantation. Methods To visualize ROS production, day 8 (short-term dormancy) and day 20 (long-term dormancy) dormant blastocysts were loaded with 1-µM 5-(and-6)-chloromethyl-2', 7'-dichlorodihydrofluorescein diacetate, acetyl ester (CM-H2DCFDA). To block autophagic activation, 3-methyladenine (3-MA) and wortmannin were used in vivo and in vitro, respectively. Results We observed that ROS production was not significantly affected by the status of dormancy; in other words, both dormant and activated blastocysts showed high levels of ROS. However, ROS production was higher in the dormant blastocysts of the long-term dormancy group than in those of the short-term group. The addition of wortmannin to dormant blastocysts in vitro and 3-MA injection in vivo significantly increased ROS production in the short-term dormant blastocysts. In the long-term dormant blastocysts, ROS levels were not significantly affected by the treatment of the autophagy inhibitor. Conclusion During delayed implantation, heightened autophagy in dormant blastocysts may be operative as a potential mechanism to reduce oxidative stress. Further, ROS may be one of the potential causes of compromised developmental competence of long-term dormant blastocysts after implantation.
    Full-text · Article · Sep 2014 · Clinical and Experimental Reproductive Medicine
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