ROS act as an upstream signal to mediate cadmium-induced mitophagy in mouse brain

Wei, Xue; Qi, Yongmei; Zhang, Xiaoning; Gu, Xueyan; Cai, Hui; Yang, Jing; Zhang, Yingmei

doi:10.1016/j.neuro.2014.11.007

Cited by 68 publications

(38 citation statements)

References 42 publications

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“…38 Recent studies have demonstrated that Cd exposure induced a significant degree of autophagy, leading to cell death in liver cells, 39 nephrocytes, 40 and neurons. 41 In contrast, we showed that Cd induced a blockade in autophagic flux resulting from the inhibition of autophagosome-lysosome fusion and a reduction in lysosomal function in Neuro-2a cells.…”

Section: Resultsmentioning

confidence: 56%

Melatonin antagonizes cadmium‐induced neurotoxicity by activating the transcription factor EB‐dependent autophagy–lysosome machinery in mouse neuroblastoma cells

Yang

et al. 2016

Journal of Pineal Research

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Cadmium (Cd), a highly ubiquitous heavy metal, induces neurotoxicity. Melatonin, a major secretory product of the pineal gland, protects against Cd-induced neurotoxicity. However, the mechanism that accounts for this protection remains to be elucidated. Herein, we exposed mouse neuroblastoma cells (Neuro-2a cells) to different concentrations of cadmium chloride (CdCl2 ) (12.5, 25, and 50 μ mol L(-1) ) for 24 hours. We showed that Cd inhibits autophagosome-lysosome fusion and impairs lysosomal function, subsequently leading to nerve cell death. In addition, Cd decreases the level of transcription factor EB (TFEB) but induces the nuclear translocation of TFEB, associated with compromised lysosomal function or a compensatory effect after the impairment of the autophagic flux. Moreover, compared to the 50-μ mol L(-1) Cd group, administration of 1 μ mol L(-1) melatonin increased "TFEB-responsive genes" (P<.05) and the levels of lysosomal-associated membrane protein (0.57±0.06 vs 1.00±0.11, P<.05), preserved lysosomal protease activity (0.52±0.01 vs 0.90±0.02, P<.05), maintained the lysosomal pH level (0.50±0.01 vs 0.87±0.05, P<.01), and enhanced autophagosome-lysosome fusion (0.05±0.00 vs 0.21±0.01, P<.01). Notably, melatonin enhanced TFEB expression (0.37±0.04 vs 0.72±0.07, P<.05) and nuclear translocation (2.81±0.08 vs 3.82±0.05, P<.05). Tfeb siRNA blocked the melatonin-mediated elevation in autophagy-lysosome machinery in Cd-induced neurotoxicity (P<.01). Taken together, these results uncover a potent role for TFEB-mediated autophagy in the pathogenesis of Cd-induced neurotoxicity, suggesting that control of the autophagic pathway by melatonin might provide an important clue for exploring potential targets for novel therapeutics of Cd-induced neurotoxicity.

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Section: Resultsmentioning

confidence: 56%

Melatonin antagonizes cadmium‐induced neurotoxicity by activating the transcription factor EB‐dependent autophagy–lysosome machinery in mouse neuroblastoma cells

Yang

et al. 2016

Journal of Pineal Research

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“…Under normal physiological conditions, the level of ROS is low in cells, and controlled by internal antioxidants without causing damage (Heiler et al, 2011;Wei et al, 2015;Momosaki et al, 2016;Andrienko et al, 2017). Since SOD and MDA are among the key biomarkers of oxidative stress, their levels directly reflect the speed and degree of lipid peroxidation, and indirectly show the level of free radical scavengers (Krupinski et al, 2003;Yan et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Protective Effect of Stachydrine Against Cerebral Ischemia-Reperfusion Injury by Reducing Inflammation and Apoptosis Through P65 and JAK2/STAT3 Signaling Pathway

Sun

Qiu

et al. 2020

Front. Pharmacol.

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Stachydrine, a constituent of Leonurus japonicus Houtt which also called Japanese motherwort has been shown to improve vascular microcirculation and ameliorate endothelial dysfunction. This study investigated the neuroprotective effect of stachydrine. Male Sprague-Dawley (SD) rats were randomly divided into sham, control, and stachydrine groups. The neurological deficit score was evaluated and the infarct size of the brain was measured using 2,3,5-triphenyltetra-zolium (TTC) chloride staining assay, and the pathological changes in the brain tissues were examined by HE staining. Nissl and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) staining were performed to assess the numbers of Nissl bodies and the levels of apoptosis in the neurons. The activities of superoxide dismutase (SOD) and the levels of malondialdehyde (MDA) were also measured. The release of inflammatory factors IL-1b and TNF-a were detected by Enzyme-linked immunosorbent assay (ELISA). Compared with the control group, the stachydrine group showed a significant prevention of neurological deficit, as indicated by the reduced infarct volume in the brain. Moreover, the stachydrine treatment reduced the activities of SOD, the levels of MDA and decreased the amount of IL-1b, and TNF-a, indicating that it could function to decrease the level of inflammation, thus reducing brain damage. The ischemic stroke model of PC12 cells was prepared via oxygen-glucose deprivation (OGD) protocol for 6 h. The expression of P65 and JAK2/STAT3 signaling pathway related proteins was measured by western blot. The treatment group was found to have the survival rate of PC12 cells improved and the release of inflammatory factors reduced when compared with the OGD group. This study demonstrated that stachydrine could improve nerve function by inhibiting the phosphorylation of P65/JAK2 and STAT3. FIGURE 1 | The chemical structure of stachydrine. Stachydrine (purity> 97%) purchased from Dalian Meilun Biology Technology Co. (Dalian, China). Li et al. Stachydrine Protects Against Cerebral Ischemia-Reperfusion InjuryFrontiers in Pharmacology | www.frontiersin.org February 2020 | Volume 11 | Article 64 absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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“…It can harm human beings in various ways, and hence, prevention and treatment for Cd poisoning is of great significance 2 , 3 .…”

Section: Introductionmentioning

confidence: 99%

“…Microtubule-associated protein light chain 3 (LC3) is considered to be a characteristic protein of autophagy 3 . When autophagy is initiated, LC3 is enzymolysized into the cytosolic type (LC3-I), which then combines with phosphatidylethanolamine (PE) to transform into the membrane type (LC3-II) 5 .…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies showed that Cd can affect the body’s (or cell’s) antioxidant system 4 , change the activity of antioxidant enzymes, and make the body (or cell) to produce a large amount of ROS, thus leading to oxidative stress 3 , 9 , 10 , 11 . In addition, Cd can induce ROS-mediated autophagy of kidney cells via a series of pathways 2 and can induce mitophagy through the ROS-mediated PTEN-induced putative kinase 1/ Parkin (PINK1/Parkin) pathway in the kidneys of mice 1 , 2 .…”

Section: Introductionmentioning

confidence: 99%

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Quercetin inhibited cadmium-induced autophagy in the mouse kidney via inhibition of oxidative stress

Yuan

et al. 2016

J Toxicol Pathol

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The objective of the current study was to explore the inhibitory effects of quercetin on cadmium-induced autophagy in mouse kidneys. Mice were intraperitoneally injected with cadmium and quercetin once daily for 3 days. The LC3-II/β-actin ratio was used as the autophagy marker, and autophagy was observed by transmission electron microscopy. Oxidative stress was investigated in terms of reactive oxygen species, total antioxidant capacity, and malondialdehyde. Cadmium significantly induced typical autophagosome formation, increased the LC3-II/β-actin ratio, reactive oxygen species level, and malondialdehyde content, and decreased total antioxidant capacity. Interestingly, quercetin markedly decreased the cadmium-induced LC3-II/β-actin ratio, reactive oxygen species levels, and malondialdehyde content, and simultaneously increased total antioxidant capacity. Cadmium can inhibit total antioxidant capacity, produce a large amount of reactive oxygen species, lead to oxidative stress, and promote lipid peroxidation, eventually inducing autophagy in mouse kidneys. Quercetin could inhibit cadmium-induced autophagy via inhibition of oxidative stress. This study may provide a theoretical basis for the treatment of cadmium injury.

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ROS act as an upstream signal to mediate cadmium-induced mitophagy in mouse brain

Cited by 68 publications

References 42 publications

Melatonin antagonizes cadmium‐induced neurotoxicity by activating the transcription factor EB‐dependent autophagy–lysosome machinery in mouse neuroblastoma cells

Melatonin antagonizes cadmium‐induced neurotoxicity by activating the transcription factor EB‐dependent autophagy–lysosome machinery in mouse neuroblastoma cells

Protective Effect of Stachydrine Against Cerebral Ischemia-Reperfusion Injury by Reducing Inflammation and Apoptosis Through P65 and JAK2/STAT3 Signaling Pathway

Quercetin inhibited cadmium-induced autophagy in the mouse kidney via inhibition of oxidative stress

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