Autophagy in Health and Disease: A Double-Edged Sword

Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan, United States
Science (Impact Factor: 33.61). 12/2004; 306(5698):990-5. DOI: 10.1126/science.1099993
Source: PubMed


Autophagy, the process by which cells recycle cytoplasm and dispose of excess or defective organelles, has entered the research
spotlight largely owing to the discovery of the protein components that drive this process. Identifying the autophagy genes
in yeast and finding orthologs in other organisms reveals the conservation of the mechanism of autophagy in eukaryotes and
allows the use of molecular genetics and biology in different model systems to study this process. By mostly morphological
studies, autophagy has been linked to disease processes. Whether autophagy protects from or causes disease is unclear. Here,
we summarize current knowledge about the role of autophagy in disease and health.

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Available from: Takahiro Shintani, Jul 15, 2014
    • "Autophagy in CDV infected cerebellum 5 processes (Levine and Klionsky 2004, Shintani and Klionsky 2004). Although autophagy participates in defense against viral, bacterial, fungal and parasitic infections, many viruses exploit autophagy for their own benefi t (Kudchodkar and Levine 2009), e.g., sindbis, human parainfl uenza 3 and varicellazoster viruses (Liang et al. 1998, Buckingham et al. 2014, Ding et al. 2014). "
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    ABSTRACT: We investigated the expression of microtubule-associated protein 1 light chain 3 (LC3) protein in the cerebellums of dogs infected with canine distemper virus (CDV) using immunohistochemistry to detect autophagy. The cerebellums of 20 dogs infected with CDV were used. Specimens showing demyelination of white matter were considered to have an acute infection, whereas specimens showing signs of severe perivascular cuffing and demyelination of white matter were classified as having chronic CDV. Cerebellar sections were immunostained with CDV and LC3 antibodies. The cytoplasm of Purkinje cells, granular layer cells, motor neurons in large cerebellar ganglia and some neurons in white matter were positive for the LC3 antibody in both the control and CDV-infected dogs. In the infected cerebellums, however, white matter was immunostained more intensely, particularly the neurons and gemistocytic astrocytes in the demyelinated areas, compared to controls. Autophagy also was demonstrated in CDV-positive cells using double immunofluorescence staining. Our findings indicate that increased autophagy in the cerebellum of dogs naturally infected with CDV may play a role in transferring the virus from cell to cell.
    Biotechnic & Histochemistry 07/2015; DOI:10.3109/10520295.2015.1064999 · 1.44 Impact Factor
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    • "It is widely reported that autophagy activation is similar to a double-edged sword with beneficial and detrimental properties (Shintani and Klionsky 2004). This also appears to be the case in the salivary glands under basal and stressed conditions. "
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    ABSTRACT: Autophagy is a catabolic process that has been shown to have a role in many cellular processes including the removal of excessive or damaged proteins and protein aggregates. The salivary glands play a critical role in oral health, and their secretory capacity may be critically intertwined with the autophagic process. This review describes the role of autophagy activation in normal salivary gland homeostasis and during the glandular stress responses of therapeutic radiation, ductal ligation, autoimmunity, and salivary gland adenoid cystic carcinoma. © International & American Associations for Dental Research 2015.
    Journal of dental research 06/2015; 94(8). DOI:10.1177/0022034515590796 · 4.14 Impact Factor
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    • "Three main forms of autophagy, including microautophagy , macroautophagy, and chaperone-mediated autophagy, have been well characterized (Mizushima and Komatsu, 2011), among which macroautophagy is thought to be the major type of autophagy that orchestrates cellular homeostasis and plays a cytoprotective role against various pathogenic insults, including nutrition deprivation, hypoxia, oxidative stress, pathogenic infection, and antitumor drug treatment (Mizushima and Komatsu, 2011). On the contrary, dysregulation and excessive activation of autophagy also result in cytotoxicity in many types of cells (Shintani and Klionsky, 2004; Mizushima et al., 2008). "
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    ABSTRACT: Methylglyoxal (MGO), a glycolytic metabolite, induces oxidative injury and apoptotic cell death that play a pathogenetic role in age-related macular degeneration (AMD). This study examined the impact of MGO on cell proliferation and autophagy flux in retinal pigment epithelium (RPE) ARPE-19 cells and elucidated the underlying mechanism. Short-term MGO exposure suppressed cell proliferation without induction of apoptotic cell death, increased production of reactive oxygen species, and potentiated H2O2-exhibited cytotoxicity in ARPE-19 cells. Conversely, pretreatment with N-acetylcysteine, a ROS scavenger, and aminoguanidine, an MGO blocker, prevented MGO-induced growth retardation. MGO significantly enhanced autophagy flux and increased intracellular accumulation of autophagosomes, which was functionally confirmed by addition of autophagy enhancer or inhibitors. Signaling kinetic observation indicated that MGO remarkably triggered phosphorylation of Akt, ERK1/2, p38 MAPK, and JNK1/2. Blockade of kinase activity demonstrated that the hyperphosphorylation of Akt, ERK1/2, JNK, and p38 MAPK were all involved in the MGO-enhanced autophagy and growth-arresting effect in ARPE-19 cells. Moreover, pretreatment with autophagic flux inhibitors including 3-methyladenine, bafilomycin A, and chloroquine effectively ameliorated MGO- but not H2O2-mediated ARPE-19 cytotoxicity. In conclusion, modulation of autophagy flux activity by using autophagic or kinase inhibitors may be an applicable modality to treat AMD. Copyright © 2015. Published by Elsevier Ltd.
    Toxicology in Vitro 05/2015; 29(7). DOI:10.1016/j.tiv.2015.05.014 · 2.90 Impact Factor
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