Autophagy attenuates copper-induced mitochondrial dysfunction by regulating oxidative stress in chicken hepatocytes

Yang, Fan; Liao, Jianzhao; Pei, Ruonan; Yu, Wenli; Han, Qing; Liu, Ying; Guo, Jianying; Hu, Lianmei; Pan, Jiang; Tang, Zhaoxin

doi:10.1016/j.chemosphere.2018.03.192

Cited by 95 publications

(42 citation statements)

References 46 publications

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“…The overproduction of ROS affects mainly biomembranous unsaturated fatty acids and decreases membrane fluidity and disrupts membrane structure and function [12]. The findings from in vitro and in vivo studies have demonstrated that Cu possesses the capacity to initiate oxidative damage [13][14][15][16][17]. Ozcelik and coworkers [18] have also found that excess Cu exposure can induce oxidative stress and suppress the antioxidant defense system in the rat liver.…”

Section: Introductionmentioning

confidence: 99%

Copper Induces Oxidative Stress and Apoptosis in the Mouse Liver

Liu

Guo

Jian

et al. 2020

Oxidative Medicine and Cellular Longevity

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Copper (Cu) is an essential trace element involved in the normal physiological processes of animals. However, excessive exposure to Cu can produce numerous detrimental impacts. The aim of this study was to investigate the effects of Cu on oxidative stress and apoptosis as well as their relationship in the mouse liver. Four-week-old ICR mice (n=240) were randomly assigned to different Cu (Cu2+-CuSO4) treatment groups (0, 4, 8, and 16 mg/kg) for periods of 21 and 42 days. The high doses of Cu exposure could induce oxidative stress, by increasing the levels of reactive oxygen species (ROS) and protein carbonyls (PC) and decreasing the activities of antisuperoxide anion (ASA) and antihydroxyl radical (AHR) and content of glutathione (GSH), as well as activities and mRNA expression levels of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px). Moreover, high doses of Cu exposure induced hepatic apoptosis via the mitochondrial apoptotic pathway, as characterized by the depolarization of mitochondrial membrane potential (MMP); significantly increased mRNA and protein expression levels of cytosolic cytochrome (Cyt c), apoptosis-inducing factor (AIF), endonuclease G (Endo G), apoptosis protease-activating factor-1 (Apaf-1), cleaved caspase-9, cleaved caspase-3, cleaved PARP, Bcl-2 antagonist killer (Bak), Bcl-2-associated X protein (Bax), and Bcl-2-interacting mediator of cell death (Bim); and decreased mRNA and protein expression levels of B-cell lymphoma-2 (Bcl-2) and Bcl-extra-large (Bcl-xL). Furthermore, the activation of the tumor necrosis factor receptor-1 (TNF-R1) signaling pathway was involved in Cu-induced apoptosis, as characterized by the significantly increased mRNA and protein expression levels of TNF-R1, Fas-associated death domain (FADD), TNFR-associated death domain (TRADD), and cleaved caspase-8. These results indicated that exposure to excess Cu could cause oxidative stress triggered by ROS overproduction and diminished antioxidant function, which in turn promoted hepatic apoptosis via mitochondrial apoptosis and that the TNF-R1 signaling pathway was also involved in the Cu-induced apoptosis.

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Section: Introductionmentioning

confidence: 99%

Copper Induces Oxidative Stress and Apoptosis in the Mouse Liver

Liu

Guo

Jian

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…In C. elegans , Cu-induced ROS robustly induced cSesn [ 64 ] that is subsequently regulating mitochondrial functions via direct association with mitochondria [ 65 ]. Therefore, we tested whether Sestrin2 is associating with mitochondria upon various mitochondria-damaging stresses, including Cu-induced heavy metal stress [ 66 ], oxidative stress H 2 O 2 [ 62 ], and mild uncoupling with CCCP [ 50 ]. We observed that ROS generated by excessive Cu induced Sestrin2 and, subsequently, autophagy in both concentration- and time-dependent manner ( Figure 2 A).…”

Section: Resultsmentioning

confidence: 99%

“…We co-expressed FLAG-tagged Sestrin2 with HA-tagged ULK1 in HEK293 cells. To activate ULK1 by mTORC1 inhibition, we treated cells with 100 nM rapamycin (Rap) for 1 h. We also treated cells with 500 µM CuSO 4 (Cu), for 6 h [ 66 ]. We then performed an immunoprecipitation using FLAG affinity resin to enrich Sestrin2 from isolated samples of interest as well as matching controls ( Figure 4 A).…”

Section: Resultsmentioning

confidence: 99%

Sestrin2 Phosphorylation by ULK1 Induces Autophagic Degradation of Mitochondria Damaged by Copper-Induced Oxidative Stress

Kim

Jeon

Kim

et al. 2020

IJMS

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Selective autolysosomal degradation of damaged mitochondria, also called mitophagy, is an indispensable process for maintaining integrity and homeostasis of mitochondria. One well-established mechanism mediating selective removal of mitochondria under relatively mild mitochondria-depolarizing stress is PINK1-Parkin-mediated or ubiquitin-dependent mitophagy. However, additional mechanisms such as LC3-mediated or ubiquitin-independent mitophagy induction by heavy environmental stress exist and remain poorly understood. The present study unravels a novel role of stress-inducible protein Sestrin2 in degradation of mitochondria damaged by transition metal stress. By utilizing proteomic methods and studies in cell culture and rodent models, we identify autophagy kinase ULK1-mediated phosphorylation sites of Sestrin2 and demonstrate Sestrin2 association with mitochondria adaptor proteins in HEK293 cells. We show that Ser-73 and Ser-254 residues of Sestrin2 are phosphorylated by ULK1, and a pool of Sestrin2 is strongly associated with mitochondrial ATP5A in response to Cu-induced oxidative stress. Subsequently, this interaction promotes association with LC3-coated autolysosomes to induce degradation of mitochondria damaged by Cu-induced ROS. Treatment of cells with antioxidants or a Cu chelator significantly reduces Sestrin2 association with mitochondria. These results highlight the ULK1-Sestrin2 pathway as a novel stress-sensing mechanism that can rapidly induce autophagic degradation of mitochondria under severe heavy metal stress.

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“…Caspase-3 is a key biomarker of apoptosis, which can be activated by both intrinsic and extrinsic apoptotic pathways and consequently lead to DNA breakdown [ 39 ]. Previous studies showed that mitochondrial dysfunction contributed to CuSO 4 -induced apoptosis in hepatocytes of chicken and rats and male germ cell line GC-1 cells [ 40 , 41 , 42 ]. The Bax up-regulation can promote the activation of mitochondrial permeability transition pores that mediated the release of cytochrome c (CytC) into the cytosol.…”

Section: Discussionmentioning

confidence: 99%

“…It has been demonstrated that CuSO 4 treatment significantly up-regulated the expression of Bax, CytC, caspase-9, and caspase-3 mRNAs and proteins followed to cause the cell apoptosis in chicken hepatocytes and male germ cells [ 44 , 45 ]. Rapamycin can partly inhibit mitochondria dysfunction (e.g., up-regulate the adenosine triphosphate (ATP) levels, mitochondrial mass, and mitochondria membrane potential) and attenuate CuSO4-induced cell apoptosis in chicken hepatocytes in vitro [ 41 ]. Consistent with previous studies, our current data showed that CuSO 4 exposure significantly up-regulated the mRNA expression of Bax, caspase-9, and caspase-3 and the activities of caspase-9 and caspase-3 ( Figure 4 ).…”

Section: Discussionmentioning

confidence: 99%

Molecular Insights of Copper Sulfate Exposure-Induced Nephrotoxicity: Involvement of Oxidative and Endoplasmic Reticulum Stress Pathways

Dai

Liu

et al. 2020

Biomolecules

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The precise pathogenic mechanism in Cu exposure-cause nephrotoxicity remains unclear. This study investigated the underlying molecular mechanism of copper sulfate (CuSO4)-induced nephrotoxicity. Mice were treated with CuSO4 at 50, 100, 200 mg/kg/day or co-treated with CuSO4 (200 mg/kg/day) and 4-phenylbutyric acid (4-PBA, 100 mg/kg/day) for 28 consecutive days. HEK293 cells were treated with CuSO4 (400 μM) with or without superoxide dismutase, catalase or 4-PBA for 24 h. Results showed that CuSO4 exposure can cause renal dysfunction and tubular necrosis in the kidney tissues of mice. CuSO4 exposure up-regulated the activities and mRNA expression of caspases-9 and -3 as well as the expression of glucose-regulated protein 78 (GRP78), GRP94, DNA damage-inducible gene 153 (GADD153/CHOP), caspase-12 mRNAs in the kidney tissues. Furthermore, superoxide dismutase and catalase pre-treatments partly inhibited CuSO4-induced cytotoxicity by decreasing reactive oxygen species (ROS) production, activities of caspases-9 and -3 and DNA fragmentations in HEK293 cells. 4-PBA co-treatment significantly improved CuSO4-induced cytotoxicity in HEK293 cells and inhibited CuSO4 exposure-induced renal dysfunction and pathology damage in the kidney tissues. In conclusion, our results reveal that oxidative stress and endoplasmic reticulum stress contribute to CuSO4-induced nephrotoxicity. Our study highlights that targeting endoplasmic reticulum and oxidative stress may offer an approach for Cu overload-caused nephrotoxicity.

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Autophagy attenuates copper-induced mitochondrial dysfunction by regulating oxidative stress in chicken hepatocytes

Cited by 95 publications

References 46 publications

Copper Induces Oxidative Stress and Apoptosis in the Mouse Liver

Copper Induces Oxidative Stress and Apoptosis in the Mouse Liver

Sestrin2 Phosphorylation by ULK1 Induces Autophagic Degradation of Mitochondria Damaged by Copper-Induced Oxidative Stress

Molecular Insights of Copper Sulfate Exposure-Induced Nephrotoxicity: Involvement of Oxidative and Endoplasmic Reticulum Stress Pathways

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