The Nuptials of Autophagy and Apoptosis –A Review

Antioxidants & Redox Signaling, 2014

Significance: The molecular machinery regulating autophagy has started becoming elucidated, and a number of studies have undertaken the task to determine the role of autophagy in cell fate determination within the context of human disease progression. Oxidative stress and redox signaling are also largely involved in the etiology of human diseases, where both survival and cell death signaling cascades have been reported to be modulated by reactive oxygen species (ROS) and reactive nitrogen species (RNS). Recent Advances: To date, there is a good understanding of the signaling events regulating autophagy, as well as the signaling processes by which alterations in redox homeostasis are transduced to the activation/regulation of signaling cascades. However, very little is known about the molecular events linking them to the regulation of autophagy. This lack of information has hampered the understanding of the role of oxidative stress and autophagy in human disease progression. Critical Issues: In this review, we will focus on (i) the molecular mechanism by which ROS/RNS generation, redox signaling, and/or oxidative stress/damage alter autophagic flux rates; (ii) the role of autophagy as a cell death process or survival mechanism in response to oxidative stress; and (iii) alternative mechanisms by which autophagy-related signaling regulate mitochondrial function and antioxidant response. Future Directions: Our research efforts should now focus on understanding the molecular basis of events by which autophagy is fine tuned by oxidation/reduction events. This knowledge will enable us to understand the mechanisms by which oxidative stress and autophagy regulate human diseases such as cancer and neurodegenerative disorders. Antioxid. Redox Signal. 21, 66-85.

Cell Death & Differentiation, 2009

Autophagy is involved in human diseases and is regulated by reactive oxygen species (ROS) including superoxide (O 2 KÀ) and hydrogen peroxide (H 2 O 2). However, the relative functions of O 2 KÀ and H 2 O 2 in regulating autophagy are unknown. In this study, autophagy was induced by starvation, mitochondrial electron transport inhibitors, and exogenous H 2 O 2. We found that O 2 KÀ was selectively induced by starvation of glucose, L-glutamine, pyruvate, and serum (GP) whereas starvation of amino acids and serum (AA) induced O 2 KÀ and H 2 O 2. Both types of starvation induced autophagy and autophagy was inhibited by overexpression of SOD2 (manganese superoxide dismutase, Mn-SOD), which reduced O 2 KÀ levels but increased H 2 O 2 levels. Starvation-induced autophagy was also inhibited by the addition of catalase, which reduced both O 2 KÀ and H 2 O 2 levels. Starvation of GP or AA also induced cell death that was increased following treatment with autophagy inhibitors 3-methyladenine, and wortamannin. Mitochondrial electron transport chain (mETC) inhibitors in combination with the SOD inhibitor 2-methoxyestradiol (2-ME) increased O 2 KÀ levels, lowered H 2 O 2 levels, and increased autophagy. In contrast to starvation, cell death induced by mETC inhibitors was increased by 2-ME. Finally, adding exogenous H 2 O 2 induced autophagy and increased intracellular O 2 KÀ but failed to increase intracellular H 2 O 2. Taken together, these findings indicate that O 2 KÀ is the major ROS-regulating autophagy.

Autophagy, 2008

electron-transport-chain inhibitors of complexes I and II induce autophagic cell death mediated by reactive oxygen species.

2006

FINE-TUNED BALANCE between protein synthesis and protein degradation inside cells is responsible for the continuous renewal of the intracellular pool of proteins (20). Two major proteolytic systems contribute to protein removal: the ubiquitin/proteasome system (extensively reviewed in other sections of this focused issue) and the lysosomal system. The lysosomal system is composed of a series of vesicular compartments with different ultrastructural and biochemical characteristics, which act coordinately to guarantee the degradation of substrate products in the "final" organelle, the lysosome (22). Thus lysosomes receive substrates for degradation, both from outside and from inside the cell, via two processes known as endocytosis and autophagy, respectively (19, 20, 33, 55, 79). This review focuses on the degradation of intracellular oxidized proteins by lysosomes, and consequently we will only discuss the autophagic process. The term autophagy groups a series of intracellular pathways that lead to the removal of cytosolic components in lysosomes. These pathways, referred to as macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA), in the case of mammalian cells, are interconnected and, in some cases, share common components (19, 20, 33, 49, 69, 79). In addition, there is growing evidence for cross-talking between these pathways and also with nonlysosomal mechanisms of degradation. Although many of the molecular players involved in these processes are still unknown, the molecular dissection of macro-and microautophagy, to some extent, has been recently made possible by screening of yeast mutants (33, 39, 79). Added to the newly identified players for this pathway, known generically as autophagy (ATG) genes (39), the introduction of yeast as a study model and, nowadays, many other model systems have contributed to the current expansion of the field. Most of the autophagic components found in yeast have orthologs in other species from amoebae to mammals (53). Genetic studies in worms (C. elegans), flies (D. melanogaster), and even in some amoebae and plants are also contributing new genes related to autophagy (4, 31, 50, 60). The proteins encoded by these genes are used now as markers for this lysosomal pathway, but in addition, mutations in these genes have revealed a new myriad of cellular functions for autophagy (43, 49, 69). In the case of chaperone-mediated autophagy (CMA) this kind of genetic screening has not been possible,

Trends in Biochemical Sciences, 2017

Significance: Autophagy, a lysosome-dependent homeostatic process inherent to cells and tissues, has emerging significance in the pathogenesis of human disease. This process enables the degradation and turnover of cytoplasmic substrates via membrane-dependent sequestration in autophagic vesicles (autophagosomes) and subsequent lysosomal delivery of cargo. Recent Advances: Selective forms of autophagy can target specific substrates (e.g., organelles, protein aggregates, lipids) for processing. Autophagy is highly regulated by oxidative stress, including exposure to altered oxygen tension, by direct and indirect mechanisms, and contributes to inducible defenses against oxidative stress. Mitochondrial autophagy (mitophagy) plays a critical role in the oxidative stress response, through maintenance of mitochondrial integrity. Critical Issues: Autophagy can impact a number of vital cellular processes including inflammation and adaptive immunity, host defense, lipid metabolism and storage, mitochondrial homeostasis, and clearance of aggregated proteins, all which may be of significance in human disease. Autophagy can exert both maladaptive and adaptive roles in disease pathogenesis, which may also be influenced by autophagy impairment. This review highlights the essential roles of autophagy in human diseases, with a focus on diseases in which oxidative stress or inflammation play key roles, including human lung, liver, kidney and heart diseases, metabolic diseases, and diseases of the cardiovascular and neural systems. Future Directions: Investigations that further elucidate the complex role of autophagy in the pathogenesis of disease will facilitate targeting this pathway for therapies in specific diseases. This paper has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

Autophagy, 2014

Endoplasmic reticulum (ER) stress-induced cell death is normally associated with activation of the mitochondrial apoptotic pathway, which is characterized by CYCS (cytochrome c, somatic) release, apoptosome formation, and caspase activation, resulting in cell death. In this study, we demonstrate that under conditions of ER stress cells devoid of CASP9/caspase-9 or BAX and BAK1, and therefore defective in the mitochondrial apoptotic pathway, still undergo a delayed form of cell death associated with the activation of caspases, therefore revealing the existence of an alternative stress-induced caspase activation pathway. We identified CASP8/caspase-8 as the apical protease in this caspase cascade, and found that knockdown of either of the key autophagic genes, ATG5 or ATG7, impacted on CASP8 activation and cell death induction, highlighting the crucial role of autophagy in the activation of this novel ER stress-induced death pathway. In line with this, we identified a protein complex ...

2014

Autophagy is a catabolic pathway of lysosomal re-cycling of cell constituens and xenobiotics by the mechanisms of sequestration of targeted biomolecules and compromised organelles within isolating membranes, i.e., autophagosomes, or protein complexes and processing them in lysosomal macinery. By this means autophagy mediates cell and organelle biogenesis, provides energy supplys and sustains systems integrity and homeostasis. Autophagy is evolutionary conserved and ubiquitouly present in eukaryotes, e.g., multicellular organisms such as fungi, plants and animals. Therefore, many details related to autophagy signaling, target-selection, autophagy flux, as well as autophagy-targeted modulation of cell and tissue biogenesis and morphogenesis have been recently investigated using in vitro models, everterbrates and lower vertebrate animals. Alsough, autolysosomal process per se is still considered to be a bulk hydrolytic degradation, a growing number of evidence indicate that autophagy biogenesis is strictly regulated by autophagy-related genes (i.e., ATG genes) and their protein products, numerous signaling cascades, adaptors, chaperones, modifiers, cell energetic conditions, and intimate interactions in the organelle networks (e.g., the endoplasmic reticulum - mitocondrial interplay). Overall, that determine cargo-selictivity to proteins and organelles as well as the pathway specificity (e.g., macroautophagy vs. chaperone-mediated autophagy). This network governs a crucial autophagy feature which is execution of barrier functions by targeting, sequestration and compartmentalisation for recycling of damaged cytotoxic constituents, acquired xenobiotics and invading pathogens. These barrier functions “arms” organisms with ability to specifically respond to starvation, oxidative, electrophilic and hypoxia stress related to acute injury and hyperinflammation; as well as to mediate innate and adaptive immunity and to control aging, infections, degenerative disease, cancer development, etc. Remarkably, the interplay between autophagy biogenesis and the endoplasmic reticulum-mitochondrial axis, cell metabolome, proteostasis and energetic machinery defines capacity of cell intrinsing resistance to stress impacts and impairments. These evidence can imply novel concepts for therapy of numerous illnesses such as cystic fibrosis, preeclampsia, drug addiction-related disease, and disfunctions of heart, lung, and nervous tissue.

Nature Reviews Drug Discovery, 2012

Autophagy is an essential, conserved lysosomal degradation pathway that controls the quality of the cytoplasm by eliminating protein aggregates and damaged organelles. It begins when doublemembraned autophagosomes engulf portions of the cytoplasm, which is followed by fusion of these vesicles with lysosomes and degradation of the autophagic contents. In addition to its vital homeostatic role, this degradation pathway is involved in various human disorders, including metabolic conditions, neurodegenerative diseases, cancers and infectious diseases. This article provides an overview of the mechanisms and regulation of autophagy, the role of this pathway in disease and strategies for therapeutic modulation.