Autophagy Plays a Cytoprotective Role During Cadmium-Induced Oxidative Damage in Primary Neuronal Cultures

Wang, Tao; Wang, Qiwen; Song, Ruilong; Zhang, Kangbao; Yuan, Yan; Bian, Jianchun; Gu, Jianhong; Liu, Zongping

doi:10.1007/s12011-015-0390-8

Cited by 35 publications

(19 citation statements)

References 40 publications

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“…The inhibitory effect of Bip siRNA on LC3, leading to GATA accumulation after Cd treatment implies that the preventive effect of autophagy on GATA4 is Bip-dependent. In our previous study, we found that 20 μM Cd induced ROS followed by autophagy in primary neurons at 6 h18. Specifically, ROS could be a upstream signal to regulate autophagy at the early stage of Cd treatment.…”

Section: Discussionmentioning

confidence: 90%

“…Protein content was determined using a BCA protein assay. Protein samples (20–80 μg) were subjected to SDS-PAGE followed by Western blotting as previously described1858. All primary antibodies were diluted at 1:1000, the corresponding HRP-conjugated secondary antibodies were diluted at 1:5000.…”

Section: Methodsmentioning

confidence: 99%

“…These findings suggest that smaller oligomeric, misfolded protein aggregates or larger fibrillar aggregates can lead to neuronal senescence17. In our previous studies examining Cd as a vital stress factor, Cd induced ROS in neurons18; these ROS can be involved in a range of events from proliferation to growth arrest or senescence19.…”

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confidence: 97%

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The ER stress regulator Bip mediates cadmium-induced autophagy and neuronal senescence

Wang

Yuan

Zou

et al. 2016

Sci Rep

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Autophagy is protective in cadmium (Cd)-induced oxidative damage. Endoplasmic reticulum (ER) stress has been shown to induce autophagy in a process requiring the unfolded protein response signalling pathways. Cd treatment significantly increased senescence in neuronal cells, which was aggravated by 3-MA or silencing of Atg5 and abolished by rapamycin. Cd increased expression of ER stress regulators Bip, chop, eIf2α, and ATF4, and activated autophagy as evidenced by upregulated LC3. Moreover, the ER stress inhibitor mithramycin inhibited the expression of ER stress protein chaperone Bip and blocked autophagic flux. Downregulating Bip significantly blocked the conversion of LC3-I to LC3-II, decreased LC3 puncta formation, and prevented the increase of senescence in PC12 cells. Interestingly, knocking down Bip regulated the expression of p-AMPK, p-AKT and p-s6k induced by Cd. BAPTA, a Bip inhibitor, decreased the expression of p-AMPK and LC3-II, but enhanced neuronal senescence. In addition, we found that siRNA for Bip enhanced GATA4 expression after 6 h Cd exposure in PC12 cells, while rapamycin treatment decreased GATA4 levels induced by 24 h Cd exposure. These results indicate that autophagy degraded GATA4 in a Bip-dependent way. Our findings suggest that autophagy regulated by Bip expression after ER stress suppressed Cd-induced neuronal senescence.

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Section: Discussionmentioning

confidence: 90%

Section: Methodsmentioning

confidence: 99%

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The ER stress regulator Bip mediates cadmium-induced autophagy and neuronal senescence

Wang

Yuan

Zou

et al. 2016

Sci Rep

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“…Perturbations in autophagy during intoxication can arise via at least two mechanisms: (i) a blockage in the fusion of autophagosomes with lysosomes; and (ii) an impairment of lysosome function that results in the perturbation of basal autophagy 4 . Recently, accumulating evidence has suggested that impaired autophagy plays a vital role in Cd-induced neurotoxicity 5 6 ; however, its cell-type specificity and mechanism of induction remain unclear.…”

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confidence: 99%

Enhancing lysosomal biogenesis and autophagic flux by activating the transcription factor EB protects against cadmium-induced neurotoxicity

Tian

et al. 2017

Sci Rep

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Cadmium (Cd), a highly ubiquitous heavy metal, is a well-known inducer of neurotoxicity. However, the mechanism underlying cadmium-induced neurotoxicity remains unclear. In this study, we found that Cd inhibits autophagosome-lysosome fusion and impairs lysosomal function by reducing the levels of lysosomal-associated membrane proteins, inhibiting lysosomal proteolysis and altering lysosomal pH, contributing to defects in autophagic clearance and subsequently leading to nerve cell death. In addition, Cd decreases transcription factor EB (TFEB) expression at both the mRNA and protein levels. Furthermore, Cd induces the nuclear translocation of TFEB and TFEB target-gene expression, associated with compromised lysosomal function or a compensatory effect after the impairment of the autophagic flux. Notably, restoration of the levels of lysosomal-associated membrane protein, lysosomal proteolysis, lysosomal pH and autophagic flux through Tfeb overexpression protects against Cd-induced neurotoxicity, and this protective effect is incompletely dependent on TFEB nuclear translocation. Moreover, gene transfer of the master autophagy regulator TFEB results in the clearance of toxic proteins and the correction of Cd-induced neurotoxicity in vivo. Our study is the first to demonstrate that Cd disrupts lysosomal function and autophagic flux and manipulation of TFEB signalling may be a therapeutic approach for antagonizing Cd-induced neurotoxicity.

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“…The mitochondrial ROS damages the mitochondria leading to impair the cellular homeostasis and apoptosis. The elimination of reactive mitochondria through mitophagy, a specific type of autophagy, involves protecting cells from apoptotic effector generated by dysfunctional mitochondria (Wang et al ., ). Our study showed that BM‐induced autophagy degraded ROS‐producing mitochondria and protected the HaCaT cells from B[a]P‐induced apoptosis.…”

Section: Discussionmentioning

confidence: 97%

Bacopa monnieri‐Induced Protective Autophagy Inhibits Benzo[a]pyrene‐Mediated Apoptosis

Das

Naik

Nayak

et al. 2016

Phytotherapy Research

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Benzo[a]pyrene (B[a]P) is capable of inducing oxidative stress and cellular injuries leading to cell death and associates with a significant risk of cancer development. Prevention of B[a]P-induced cellular toxicity with herbal compound through regulation of mitochondrial oxidative stress might protect cell death and have therapeutic benefit to human health. In this study, we demonstrated the cytoprotective role of Bacopa monnieri (BM) against B[a]P-induced apoptosis through autophagy induction. Pretreatment with BM rescued the reduction in cell viability in B[a]P-treated human keratinocytes (HaCaT) cells indicating the cytoprotective potential of BM against B[a]P. Moreover, BM was found to inhibit B[a]P-mediated reactive oxygen species (ROS)-induced apoptosis activation in HaCaT cells. Furthermore, BM was found to preserve mitochondrial membrane potential and inhibited release of cytochrome c in B[a]P-treated HaCaT cells. Bacopa monnieri induced protective autophagy; we knocked down Beclin-1, and data showed that BM was unable to protect from B[a]P-induced mitochondrial ROS-mediated apoptosis in Beclin-1-deficient HaCaT cells. Moreover, we established that B[a]P-induced damaged mitochondria were found to colocalize and degraded within autolysosomes in order to protect HaCaT cells from mitochondrial injury. In conclusion, B[a]P-induced apoptosis was rescued by BM treatment and provided cytoprotection through Beclin-1-dependent autophagy activation. Copyright © 2016 John Wiley & Sons, Ltd.

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Autophagy Plays a Cytoprotective Role During Cadmium-Induced Oxidative Damage in Primary Neuronal Cultures

Cited by 35 publications

References 40 publications

The ER stress regulator Bip mediates cadmium-induced autophagy and neuronal senescence

The ER stress regulator Bip mediates cadmium-induced autophagy and neuronal senescence

Enhancing lysosomal biogenesis and autophagic flux by activating the transcription factor EB protects against cadmium-induced neurotoxicity

Bacopa monnieri‐Induced Protective Autophagy Inhibits Benzo[a]pyrene‐Mediated Apoptosis

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