Oxidative injury triggers autophagy in astrocytes: The role of endogenous zinc

Lee, Sook-Jeong; Cho, Kyung Sook; Koh, Jae‐Young

doi:10.1002/glia.20854

Cited by 105 publications

(90 citation statements)

References 31 publications

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“…Chelatable Zn 2ϩ fluorescence is observed within lysosomal lumen and vacuolar lumen. These results intriguingly resemble what has been reported as a Zn 2ϩ buildup in ethambutol-induced vacuoles in retinal cells (13,14) and hydrogen peroxide-induced autophagic vacuoles in astrocytes (12). Chelatable Zn 2ϩ appears to mediate autophagic and lysosomal vacuole formation in these aforementioned cells because Zn 2ϩ chelation reduces such an effect, but whether it could also be involved in vacuolar formation upon the loss of TRPML1 function remains to be determined.…”

Section: Discussionsupporting

confidence: 86%

“…Furthermore, endosomes, autophagosomes, and lysosomes, which are critical organelles involved in the recycling and degradation of many proteins, are known compartments where chelatable Zn 2ϩ accumulates upon cellular perturbation (10 -12). Interestingly, chelatable Zn 2ϩ appears to mediate vacuolar formation in primary retinal cells exposed to ethambutol (an antituberculosis drug known for its ocular toxicity) (13,14) and autophagic vacuole formation in astrocytes upon exposure to hydrogen peroxide (12). Consequently, high levels of chelatable Zn 2ϩ accrue in ethambutol-induced vacuoles, which induce lysosomal membrane permeabilization and retinal cell death (13).…”

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confidence: 99%

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Zinc Dyshomeostasis Is Linked with the Loss of Mucolipidosis IV-associated TRPML1 Ion Channel

Eichelsdoerfer

Evans

Slaugenhaupt

et al. 2010

Journal of Biological Chemistry

102

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Chelatable zinc is important in brain function, and its homeostasis is maintained to prevent cytotoxic overload. However, certain pathologic events result in intracellular zinc accumulation in lysosomes and mitochondria. Abnormal lysosomes and mitochondria are common features of the human lysosomal storage disorder known as mucolipidosis IV (MLIV). MLIV is caused by the loss of TRPML1 ion channel function. MLIV cells develop large hyperacidic lysosomes, membranous vacuoles, mitochondrial fragmentation, and autophagic dysfunction. Here, we observed that RNA interference of mucolipin-1 gene (TRPML1) in HEK-293 cells mimics the MLIV cell phenotype consisting of large lysosomes and membranous vacuoles that accumulate chelatable zinc. To show that abnormal chelatable zinc levels are indeed correlated with MLIV pathology, we quantified its concentration in cultured MLIV patient fibroblast and control cells with a spectrofluorometer using N-(6-methoxy-8-quinolyl)-p-toluene sulfonamide fluorochrome. We found a significant increase of chelatable zinc levels in MLIV cells but not in control cells. Furthermore, we quantified various metal isotopes in whole brain tissue of TRPML1 ؊/؊ null mice and wild-type littermates using inductively coupled plasma mass spectrometry and observed that the zinc-66 isotope is markedly elevated in the brain of TRPML1 ؊/؊ mice when compared with controls. In conclusion, we show for the first time that the loss of TRPML1 function results in intracellular chelatable zinc dyshomeostasis. We propose that chelatable zinc accumulation in large lysosomes and membranous vacuoles may contribute to the pathogenesis of the disease and progressive cell degeneration in MLIV patients.Zinc (Zn 2ϩ ) is a redox-inert yet crucial trace element for virtually all organisms. Zn 2ϩ is second to iron in biological trace metal abundance and is known to play an important role in human brain function (1, 2). Some enzymes require Zn 2ϩ as co-factors, but many proteins use it for structural stability and thus are tightly bound (non-chelatable form) (3). A chelatable pool of Zn 2ϩ is present in cells, most notably in glutamatergic vesicles, and gets released at the neuronal synapse during normal and pathological states (4, 5). Because high levels of chelatable Zn 2ϩ or any trace metals produce cellular and mitochondrial toxicity (1, 6, 7), it is imperative that Zn 2ϩ homeostasis is actively maintained inside and outside of the cells. Certain pathological events such as epilepsy, cerebral stroke, and traumatic brain injury result in uncontrolled release and accumulation of chelatable Zn 2ϩ in neurons (1, 8) via voltage-gated or calcium-permeable ion channels (9). Furthermore, endosomes, autophagosomes, and lysosomes, which are critical organelles involved in the recycling and degradation of many proteins, are known compartments where chelatable Zn 2ϩ accumulates upon cellular perturbation (10 -12). Interestingly, chelatable Zn 2ϩ appears to mediate vacuolar formation in primary retinal cells exposed to ethambutol (an anti...

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Section: Discussionsupporting

confidence: 86%

mentioning

confidence: 99%

Zinc Dyshomeostasis Is Linked with the Loss of Mucolipidosis IV-associated TRPML1 Ion Channel

Eichelsdoerfer

Evans

Slaugenhaupt

et al. 2010

Journal of Biological Chemistry

102

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“…Impairment of the autophagy pathway by ablation of Atg7 in astrocytes in the inflammatory environment amplifies the response to produce more neurotoxic factors such as ROS, which induces astrocytic cell death [22,80] . mTOR in the astrocyte may play a protective role in ischemia via its downstream kinase S6K1 [81] .…”

Section: Autophagy In Glial Cellsmentioning

confidence: 99%

Role of autophagy in the pathogenesis of multiple sclerosis

Liang

2015

Neurosci. Bull.

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Autophagy plays an important role in maintaining the cellular homeostasis. One of its functions is to degrade unnecessary organelles and proteins for energy recycling or amino-acids for cell survival. Ablation of autophagy leads to neurodegeneration. Multiple sclerosis (MS), a permanent neurological impairment typical of chronic inflammatory demyelinating disorder, is an auto-immune disease of the central nervous system (CNS). Autophagy is tightly linked to the innate and adaptive immune systems during the autoimmune process, and several studies have shown that autophagy directly participates in the progress of MS or experimental autoimmune encephalomyelitis (EAE, a mouse model of MS). Dysfunction of mitochondria that intensively infl uences the autophagy pathway is one of the important factors in the pathogenesis of MS. Autophagy-related gene (ATG) 5 and immune-related GTPase M (IRGM) 1 are increased, while ATG16L2 is decreased, in T-cells in EAE and active relapsing-remitting MS brains. Administration of rapamycin, an inhibitor of mammalian target of rapamycin ( mTOR), ameliorates relapsing-remitting EAE. Infl ammation and oxidative stress are increased in MS lesions and EAE, but Lamp2 and the LC3-II/LC3-I ratio are decreased. Furthermore, autophagy in various glial cells plays important roles in regulating neuro-infl ammation in the CNS, implying potential roles in MS. In this review, we discuss the role of autophagy in the peripheral immune system and the CNS in neuroinfl ammation associated with the pathogenesis of MS. Keywords: autophagy; multiple sclerosis; neuro-infl ammation ·Review· IntroductionAutophagy, a lysosome-dependent degradation pathway, contributes to maintaining cellular homeostasis. Clearance of long-lived proteins, unnecessary organelles, and aggregate-prone proteins is mainly executed by autophagy for recycling cellular materials [1] . There are three subtypes of autophagy, macroautophagy, chaperone-mediated autophagy (CMA), and mitophagy. Macroautophagy is the major type for selective degradation of protein aggregates or misfolded proteins. The ubiquitin-labeled proteins are recognized by autophagy receptors, such as p62, neighbor of BRCA1 gene 1 (NBR1), and NIP3-like protein X (NIX), to form autophagosomes that then fuse with lysosomes for degradation. Many autophagy-related genes function during this process, such as Unc51-like kinase (ULK1) and autophagy-related gene (ATG) 5. Mammalian target of rapamycin (mTOR) represses autophagy by regulating ULK1 phosphorylation, while AMPK activates this process.CMA mediates the degradation of large molecular-weight proteins containing the KFERQ motif recognized by heat shock cognate protein of 70 kDa (HSC70). The substrate is then escorted to lysosome-associated membrane protein 2 (LAMP2A) for lysosomal degradation. Mitophagy is responsible for the degradation of damaged mitochondria.Parkin and PINK1 play critical roles in this process [2] . More Neurosci Bull August 1, 2015, 31(4): 435-444 436 attention has been paid to autophagy in the path...

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“…Another common intracellular stress that effectively leads to the induction of autophagy is oxidative stress. More recently, it has been demonstrated that oxidative stress activates autophagy in dopaminergic neuronal cell lines and cultured primary astrocytes [46][47][48] . Together, ER stress and oxidative stress may be important mechanisms of autophagy activation in ischemic brain injury.…”

Section: Er Stress and Oxidative Stressmentioning

confidence: 99%

Death and survival of neuronal and astrocytic cells in ischemic brain injury: a role of autophagy

Zhang

2011

Acta Pharmacol Sin

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Autophagy is a highly regulated cellular mechanism that leads to degradation of long-lived proteins and dysfunctional organelles. The process has been implicated in a variety of physiological and pathological conditions relevant to neurological diseases. Recent studies show the existence of autophagy in cerebral ischemia, but no consensus has yet been reached regarding the functions of autophagy in this condition. This article highlights the activation of autophagy during cerebral ischemia and/or reperfusion, especially in neurons and astrocytes, as well as the role of autophagy in neuronal or astrocytic cell death and survival. We propose that physiological levels of autophagy, presumably caused by mild to modest hypoxia or ischemia, appear to be protective. However, high levels of autophagy caused by severe hypoxia or ischemia and/or reperfusion may cause self-digestion and eventual neuronal and astrocytic cell death. We also discuss that oxidative and endoplasmic reticulum (ER) stresses in cerebral hypoxia or ischemia and/or reperfusion are potent stimuli of autophagy in neurons and astrocytes. In addition, we review the evidence suggesting a considerable overlap between autophagy on one hand, and apoptosis, necrosis and necroptosis on the other hand, in determining the outcomes and final morphology of damaged neurons and astrocytes.

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Oxidative injury triggers autophagy in astrocytes: The role of endogenous zinc

Cited by 105 publications

References 31 publications

Zinc Dyshomeostasis Is Linked with the Loss of Mucolipidosis IV-associated TRPML1 Ion Channel

Zinc Dyshomeostasis Is Linked with the Loss of Mucolipidosis IV-associated TRPML1 Ion Channel

Role of autophagy in the pathogenesis of multiple sclerosis

Death and survival of neuronal and astrocytic cells in ischemic brain injury: a role of autophagy

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