Autophagy as a Stress-Response and Quality-Control Mechanism: Implications for Cell Injury and Human Disease
Department of Pathology, Helen Diller Family Comprehensive Cancer Center, and Biomedical Sciences Graduate Program, University of California, San Francisco, California 94143 Annual Review of Pathology Mechanisms of Disease
(Impact Factor: 18.75).
10/2012; 8(1). DOI: 10.1146/annurev-pathol-020712-163918
Autophagy, a vital catabolic process that degrades cytoplasmic components within the lysosome, is an essential cytoprotective response to pathologic stresses that occur during diseases such as cancer, ischemia, and infection. In addition to its role as a stress-response pathway, autophagy plays an essential quality-control function in the cell by promoting basal turnover of long-lived proteins and organelles, as well as by selectively degrading damaged cellular components. This homeostatic function protects against a wide variety of diseases, including neurodegeneration, myopathy, liver disease, and diabetes. This review discusses our current understanding of these two principal functions of autophagy and describes in detail how alterations in autophagy promote human disease. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease Volume 8 is January 24, 2013. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
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- "Autophagy is an evolutionarily conserved process in which organelles and proteins are sequestered into a double-membrane-bound autophagosome, and delivered to the lysosome for degradation. Recent reports reveal that autophagy is involved in diverse pathophysiological processes, including cell survival, aging, neurodegeneration, cancer and the clearance of intracellular pathogen131415. Accumulating evidence indicates that autophagy may function as a crucial anti-TB strategy of the host, although these data are mainly obtained from the investigation on BCG or standard H37Rv strain. On the other hand, it is also suggested that through the intimate and persistent interaction with its human host, Mtb may have evolved strategies to counter the antibacterial effect of autophagy[9,10,12,161718. "
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Tuberculosis (TB) represents a major global health problem. The prognosis of clinically active tuberculosis depends on the complex interactions between Mycobacterium tuberculosis (Mtb) and its host. In recent years, autophagy receives particular attention for its role in host defense against intracellular pathogens, including Mtb. In present study, we aim to investigate the relationship of autophagy induction by clinical isolates of Mtb with the clinical outcomes in patients with TB.
We collected 185 clinical isolates of Mtb, and determined the effect of these Mtb isolates on autophagy induction in macrophages. It was found that most of clinical isolates of Mtb were able to induce autophagosome formation in macrophages, however, the autophagy-inducing ability varied significantly among different isolates. Of importance, our results revealed that patients infected by Mtb with poor autophagy-inducing ability displayed more severe radiographic extent of disease (p<0.001), and were more likely to have unfavorable treatment outcomes (p<0.001). No significant association was observed between the extent of Mtb-induced autophagy with some socio-demographic characteristics (such as gender, age and tobacco consumption), and some laboratory tests (such as hemoglobin, leukocyte count and erythrocyte sedimentation rate). Furthermore, results from logistic regression analysis demonstrated that the defect in autophagy induction by clinical isolates of Mtb was an independent risk factor for far-advanced radiographic disease (aOR 4.710 [1.93-11.50]) and unfavorable treatment outcomes (aOR 8.309 [2.22-28.97]) in TB.
These data indicated that the defect in autophagy induction by Mtb isolates increased the risk of poor clinical outcomes in TB patients, and detection of clinical isolates-induced autophagosome formation might help evaluate the TB outcomes.
Available from: Jakub Hanus
- "Autophagy is a catabolic process aimed at degrading damaged organelles, proteins and cellular debris by engulfing them into a double membrane vesicle called the autophagosome and eliminating them by posterior fusion with the lysosome (Flores-Bellver et al., 2014). Overactive autophagy may be cytotoxic (Murrow and Debnath, 2013). Autophagy is characterized by the formation of the autophagosome containing lipidated LC3. "
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ABSTRACT: Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly. The underlying mechanism of non-neovascular AMD (dry AMD), also named geographic atrophy (GA) remains unclear and the mechanism of retinal pigment epithelial (RPE) cell death in AMD is controversial. We review the history and recent progress in understanding the mechanism of RPE cell death induced by oxidative stress, in AMD mouse models, and in AMD patients. Due to the limitation of toolsets to distinguish between apoptosis and necroptosis (or necrosis), most previous research concludes that apoptosis is a major mechanism for RPE cell death in response to oxidative stress and in AMD. Recent studies suggest necroptosis as a major mechanism of RPE cell death in response to oxidative stress. Moreover, ultrastructural and histopathological studies support necrosis as major mechanism of RPE cells death in AMD. In this review, we discuss the mechanism of RPE cell death in response to oxidative stress, in AMD mouse models, and in human AMD patients. Based on the literature, we hypothesize that necroptosis is a major mechanism for RPE cell death in response to oxidative stress and in AMD.
Available from: Parco Siu
- "Our observed increased LC3-II to LC3-I ratio and reduced accumulation of p62 indicated that autophagic flux was reactivated in the UnAG-treated diabetic muscle. Accumulation of p62 has been demonstrated to disequilibrate cellular homeostasis in different tissues leading to diseases such as diabetes, myopathy, and dementia (reviewed in). The crosstalk between autophagic and insulin signaling pathways in skeletal muscle has not been fully addressed. "
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ABSTRACT: Impairment of insulin signaling in skeletal muscle detrimentally affects insulin-stimulated disposal of glucose. Restoration of insulin signaling in skeletal muscle is important as muscle is one of the major sites for disposal of blood glucose. Recently, unacylated ghrelin (UnAG) has received attention in diabetic research due to its favorable actions on improving glucose tolerance, glycemic control, and insulin sensitivity. The investigation of UnAG has entered phase Ib clinical trial in type 2 diabetes and phase II clinical trial in hyperphagia in Prader-Willi syndrome. Nonetheless, the precise mechanisms responsible for the anti-diabetic actions of UnAG remain incompletely understood. In this study, we examined the effects of UnAG on restoring the impaired insulin signaling in skeletal muscle of db/db diabetic mice. Our results demonstrated that UnAG effectively restored the impaired insulin signaling in diabetic muscle. UnAG decreased insulin receptor substrate (IRS) phosphorylation, increased protein kinase B (Akt) phosphorylation, and, hence, suppressed mTOR signaling. Consequently, UnAG enhanced Glut4 localization and increased PDH activity in the diabetic skeletal muscle. Intriguingly, our data indicated that UnAG normalized the suppressed autophagic signaling in diabetic muscle. In conclusion, our findings illustrated that UnAG restored the impaired insulin and autophagic signaling in skeletal muscle of diabetic mice, which are valuable to understand the underlying mechanisms of the anti-diabetic action of UnAG at peripheral skeletal muscle level.
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