Dynamin 1-like-dependent mitochondrial fission initiates overactive mitophagy in the hepatotoxicity of cadmium

Pi, Huifeng; Xu, Shangcheng; Zhang, Lei; Guo, Pengyi; Li, Yuming; Xie, Jia; Tian, Li; He, Mindi; Lu, Yonghui; Li, Min; Zhang, Yanwen; Zhong, Min; Xiang, Yang; Deng, Linhong; Zhou, Zhou; Yu, Zhengping

doi:10.4161/auto.25665

Cited by 122 publications

(86 citation statements)

References 75 publications

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“…These results suggest that BPA induced autophagic flux rather than inhibiting autophagic proteolysis. Similarly, other toxicants, such as ethanol (34) and cadmium (30), were also found to increase GFP-LC3 puncta and decreased levels of p62.…”

Section: Discussionmentioning

confidence: 87%

“…cancer and neurological and neurodegenerative disorders, such as Parkinson and Alzheimer disease) (25,27,28). Recent studies have found that several environmental toxicants, such as arsenic (29), cadmium, chromium (30,31), dibenzofuran (32), paraquat (33), and ethanol (34,35), cause alterations in the basal levels of autophagy, leading to cellular toxicity. Autophagy acts as a cardinal process and interconnects several cell survival pathways (viz.…”

Section: Bisphenol-a (Bpa)mentioning

confidence: 99%

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Activation of Autophagic Flux against Xenoestrogen Bisphenol-A-induced Hippocampal Neurodegeneration via AMP kinase (AMPK)/Mammalian Target of Rapamycin (mTOR) Pathways

Agarwal

Tiwari

Seth

et al. 2015

Journal of Biological Chemistry

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Background:The effects of xenoestrogen bisphenol-A on autophagy, and association with oxidative stress and apoptosis are still elusive. Results: Transient activation of autophagy protects against bisphenol-A-induced neurodegeneration via AMPK activation and mTOR down-regulation. Conclusion: Autophagy induction against bisphenol-A is an early cell's tolerance response. Significance: Autophagy provides an imperative biological marker for evaluation of neurotoxicity by xenoestrogen.

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Section: Discussionmentioning

confidence: 87%

Section: Bisphenol-a (Bpa)mentioning

confidence: 99%

Activation of Autophagic Flux against Xenoestrogen Bisphenol-A-induced Hippocampal Neurodegeneration via AMP kinase (AMPK)/Mammalian Target of Rapamycin (mTOR) Pathways

Agarwal

Tiwari

Seth

et al. 2015

Journal of Biological Chemistry

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show abstract

“…We next examined the change in the SQSTM1 protein levels. This protein is selectively incorporated into autophagosomes via direct binding to LC3 and is efficiently degraded by autophagy [26]. We observed an evident dose-dependent decrease in the SQSTM1 protein levels in SW1353 cells that were treated with salidroside, confirming that autophagic flux was intact in the salidroside-treated cell (Fig.…”

Section: Resultssupporting

confidence: 72%

Inhibiting ROS-TFEB-Dependent Autophagy Enhances Salidroside-Induced Apoptosis in Human Chondrosarcoma Cells

Zeng

Xiao

Cai

et al. 2017

Cell Physiol Biochem

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Background/Aims: Autophagy modulation has been considered a potential therapeutic strategy for human chondrosarcoma, and a previous study indicated that salidroside exhibits significant anti-carcinogenic activity. However, the ability of salidroside to induce autophagy and its role in human chondrosarcoma cell death remains unclear. Methods: We exposed SW1353 cells to different concentrations of salidroside (0.5, 1 and 2 mM) for 24 h. RT-PCR, Western-blotting, Immunocytofluorescence, and Luciferase Reporter Assays were used to evaluate whether salidroside activated the TFEB-dependent autophagy. Results: We show that salidroside induced significant apoptosis in the human chondrosarcoma cell line SW1353. In addition, we demonstrate that salidroside-induced an autophagic response in SW1353 cells, as evidenced by the upregulation of LC3-II and downregulation of P62. Moreover, pharmacological or genetic blocking of autophagy enhanced salidroside -induced apoptosis, indicating the cytoprotective role of autophagy in salidroside-treated SW1353 cells. Salidroside also induced TFEB ^(Ser142) dephosphorylation, subsequently to activated TFEB nuclear translocation and increase of TFEB reporter activity, which contributed to lysosomal biogenesis and the expression of autophagy-related genes. Importantly, we found that salidroside triggered the generation of ROS in SW1353 cells. Furthermore, NAC, a ROS scavenger, abrogated the effects of salidroside on TFEB-dependent autophagy. Conclusions: These data demonstrate that salidroside increased TFEB-dependent autophagy by activating ROS signaling pathways in human chondrosarcoma cells. These data also suggest that blocking ROS-TFEB-dependent autophagy to enhance the activity of salidroside warrants further attention in treatment of human chondrosarcoma cells.

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“…However, in the present study we observed that BPA-induced cytotoxicity results from alteration in the mitochondrial dynamics involving enhanced mitochondrial fission and increased levels of mitochondrial fission protein Drp-1. Several previous studies suggested that translocation of Drp-1 in the mitochondria enhances fission and apoptosis (25,(41)(42)(43)(44). Similarly, enhanced Drp-1 mitochondrial translocation is also associated with enhanced neurodegeneration and pathogenesis of neurodegenerative disorders (25,45,46).…”

Section: Drp-1 Is Involved In the Regulation Of Bpa-induced Mitochondmentioning

confidence: 93%

Dynamin-related Protein 1 Inhibition Mitigates Bisphenol A-mediated Alterations in Mitochondrial Dynamics and Neural Stem Cell Proliferation and Differentiation

Agarwal

Yadav

Tiwari

et al. 2016

Journal of Biological Chemistry

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The regulatory dynamics of mitochondria comprises well orchestrated distribution and mitochondrial turnover to maintain the mitochondrial circuitry and homeostasis inside the cells. Several pieces of evidence suggested impaired mitochondrial dynamics and its association with the pathogenesis of neurodegenerative disorders. We found that chronic exposure of synthetic xenoestrogen bisphenol A (BPA), a component of consumer plastic products, impaired autophagy-mediated mitochondrial turnover, leading to increased oxidative stress, mitochondrial fragmentation, and apoptosis in hippocampal neural stem cells (NSCs). It also inhibited hippocampal derived NSC proliferation and differentiation, as evident by the decreased number of BrdU-and ␤-III tubulin-positive cells. All these effects were reversed by the inhibition of oxidative stress using N-acetyl cysteine. BPA up-regulated the levels of Drp-1 (dynamin-related protein 1) and enhanced its mitochondrial translocation, with no effect on Fis-1, Mfn-1, Mfn-2, and Opa-1 in vitro and in the hippocampus. Moreover, transmission electron microscopy studies suggested increased mitochondrial fission and accumulation of fragmented mitochondria and decreased elongated mitochondria in the hippocampus of the rat brain. Impaired mitochondrial dynamics by BPA resulted in increased reactive oxygen species and malondialdehyde levels, disruption of mitochondrial membrane potential, and ATP decline. Pharmacological (Mdivi-1) and genetic (Drp-1siRNA) inhibition of Drp-1 reversed BPA-induced mitochondrial dysfunctions, fragmentation, and apoptosis. Interestingly, BPAmediated inhibitory effects on NSC proliferation and neuronal differentiations were also mitigated by Drp-1 inhibition. On the other hand, Drp-1 inhibition blocked BPA-mediated Drp-1 translocation, leading to decreased apoptosis of NSC. Overall, our studies implicate Drp-1 as a potential therapeutic target against BPA-mediated impaired mitochondrial dynamics and neurodegeneration in the hippocampus.

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Dynamin 1-like-dependent mitochondrial fission initiates overactive mitophagy in the hepatotoxicity of cadmium

Cited by 122 publications

References 75 publications

Activation of Autophagic Flux against Xenoestrogen Bisphenol-A-induced Hippocampal Neurodegeneration via AMP kinase (AMPK)/Mammalian Target of Rapamycin (mTOR) Pathways

Activation of Autophagic Flux against Xenoestrogen Bisphenol-A-induced Hippocampal Neurodegeneration via AMP kinase (AMPK)/Mammalian Target of Rapamycin (mTOR) Pathways

Inhibiting ROS-TFEB-Dependent Autophagy Enhances Salidroside-Induced Apoptosis in Human Chondrosarcoma Cells

Dynamin-related Protein 1 Inhibition Mitigates Bisphenol A-mediated Alterations in Mitochondrial Dynamics and Neural Stem Cell Proliferation and Differentiation

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