Industrial activities such as smelting emissions,mineral combustion and industrial wastewater discharge might lead to copper pollution in the environment.This kind of copper pollution has harmful effects on aquatic o ...Industrial activities such as smelting emissions,mineral combustion and industrial wastewater discharge might lead to copper pollution in the environment.This kind of copper pollution has harmful effects on aquatic o rganisms,plants and animals through direct or indirect exposure.However,the current understanding of the toxicity of copper is rather limited.Copper overload can perturb intracellular homeostasis and induce oxidative stress and e ven cell death.Recently,cuproptosis has been identified as a copper-dependent form of cell death induced by o xidative stress in mitochondria.We uncover here that zinc transporter 1(ZNT1)is an important regulator involved in cuproptosis.Firstly,we established the copper overload-induced cell death model with the overexpression of copper importer SLC31A1 in HeLa cells.Using this model,we conducted unbiased genome-wide CRISPR-Cas9 screens in cells treated with copper.Our results revealed a significant enrichment of ZNT1 gene in both library A and library B plasmids.Knocking out of ZNT1 in HeLa cells notably prevented cuproptosis.Subsequent knockout of metal transcription factor 1(MTF1)in ZNT1-deficient cells nearly abolished their ability to resist copper-induced cell death.However,overexpression of metallothionein 1X(MT1X)in the double-knockout cells could p artially restored the resistance to cuproptosis by loss of MTF1.Mechanistically,knockout of ZNT1 could promote MT1X expression by activating MTF1.As a consequence,the interaction between MT1X and copper was e nhanced,reducing the flow of copper into mitochondria and eliminating mitochondria damage.Taken together,this study reveals the important role of ZNT1 in cuproptosis and shows MTF1-MT1X axis mediated resistance to c uproptosis.Moreover,our study will help to understand the regulatory mechanism of cellular and systemic copper homeostasis under copper overload,and present insights into novel treatments for damages caused by both genetic copper overload diseases and environmental copper contamination.展开更多
利用Caco-2细胞模型研究不同浓度硫酸铜,微米氧化铜,纳米氧化铜(铜水平2、4、8、16 mg/L)对细胞铜-ATP酶、二价金属离子转运体1(Divalent Metal Transporter 1,DMT1)、金属硫蛋白(metallothionein,MT)含量的影响。结果显示,培养液中添...利用Caco-2细胞模型研究不同浓度硫酸铜,微米氧化铜,纳米氧化铜(铜水平2、4、8、16 mg/L)对细胞铜-ATP酶、二价金属离子转运体1(Divalent Metal Transporter 1,DMT1)、金属硫蛋白(metallothionein,MT)含量的影响。结果显示,培养液中添加铜离子能提高Caco-2细胞铜-ATP酶、MT含量,低浓度铜离子能提高细胞DMT1含量,高浓度铜离子降低细胞DMT1含量。纳米氧化铜对几种铜转运蛋白的作用与硫酸铜类似,但纳米氧化铜对铜-ATP酶、MT、DMT1含量的影响更加明显。展开更多
The Duobaoshan mine area in Heilongjiang is located in the northeast section of Xingmeng orogenic belt and is in the west side of Hegang Mountain-Heihe fault zone. There exist many deposits in this area,and its metall...The Duobaoshan mine area in Heilongjiang is located in the northeast section of Xingmeng orogenic belt and is in the west side of Hegang Mountain-Heihe fault zone. There exist many deposits in this area,and its metallogenic conditions are superior,which has been one of the hotspots in geological prospecting and metallogenic research in Northeast China. On the basis of previous studies,the authors used the EH-4 electromagnetic imaging system to carry out the data acquisition of three survey lines in Woduhe Village,Duobaoshan Town,Nenjiang County. Through the analysis of apparent resistivity section under TE and TM polarization modes,integrating regional geological data,it is concluded that:(1) the electrical characteristics of the metal ore in this area show a relatively low resistance,and according to its resistivity difference with surrounding rocks,the geometrical structures and apparent resistivity parameters of the low resistivity bodies in the lower section of the survey line are defined,and the electrical anomalies can be identified;(2)faults F1 and F2 may have a good metallogenic environment,so they are recommended for further exploration;(3) low resistance metal ore bodies have good correlation with local small structures or faults,which may play an iconic role for the delineation of key target areas;(4) in the process of using apparent resistivity to define the geometric structures of ore bodies underground,comprehensive analysis integrating the advantages of TE and TM models should be carry out to achieve more reliable inversion results.展开更多
文摘Industrial activities such as smelting emissions,mineral combustion and industrial wastewater discharge might lead to copper pollution in the environment.This kind of copper pollution has harmful effects on aquatic o rganisms,plants and animals through direct or indirect exposure.However,the current understanding of the toxicity of copper is rather limited.Copper overload can perturb intracellular homeostasis and induce oxidative stress and e ven cell death.Recently,cuproptosis has been identified as a copper-dependent form of cell death induced by o xidative stress in mitochondria.We uncover here that zinc transporter 1(ZNT1)is an important regulator involved in cuproptosis.Firstly,we established the copper overload-induced cell death model with the overexpression of copper importer SLC31A1 in HeLa cells.Using this model,we conducted unbiased genome-wide CRISPR-Cas9 screens in cells treated with copper.Our results revealed a significant enrichment of ZNT1 gene in both library A and library B plasmids.Knocking out of ZNT1 in HeLa cells notably prevented cuproptosis.Subsequent knockout of metal transcription factor 1(MTF1)in ZNT1-deficient cells nearly abolished their ability to resist copper-induced cell death.However,overexpression of metallothionein 1X(MT1X)in the double-knockout cells could p artially restored the resistance to cuproptosis by loss of MTF1.Mechanistically,knockout of ZNT1 could promote MT1X expression by activating MTF1.As a consequence,the interaction between MT1X and copper was e nhanced,reducing the flow of copper into mitochondria and eliminating mitochondria damage.Taken together,this study reveals the important role of ZNT1 in cuproptosis and shows MTF1-MT1X axis mediated resistance to c uproptosis.Moreover,our study will help to understand the regulatory mechanism of cellular and systemic copper homeostasis under copper overload,and present insights into novel treatments for damages caused by both genetic copper overload diseases and environmental copper contamination.
文摘利用Caco-2细胞模型研究不同浓度硫酸铜,微米氧化铜,纳米氧化铜(铜水平2、4、8、16 mg/L)对细胞铜-ATP酶、二价金属离子转运体1(Divalent Metal Transporter 1,DMT1)、金属硫蛋白(metallothionein,MT)含量的影响。结果显示,培养液中添加铜离子能提高Caco-2细胞铜-ATP酶、MT含量,低浓度铜离子能提高细胞DMT1含量,高浓度铜离子降低细胞DMT1含量。纳米氧化铜对几种铜转运蛋白的作用与硫酸铜类似,但纳米氧化铜对铜-ATP酶、MT、DMT1含量的影响更加明显。
基金Supported by National Key Basic Research Program of China(973 Program)(No.3B813C254423)
文摘The Duobaoshan mine area in Heilongjiang is located in the northeast section of Xingmeng orogenic belt and is in the west side of Hegang Mountain-Heihe fault zone. There exist many deposits in this area,and its metallogenic conditions are superior,which has been one of the hotspots in geological prospecting and metallogenic research in Northeast China. On the basis of previous studies,the authors used the EH-4 electromagnetic imaging system to carry out the data acquisition of three survey lines in Woduhe Village,Duobaoshan Town,Nenjiang County. Through the analysis of apparent resistivity section under TE and TM polarization modes,integrating regional geological data,it is concluded that:(1) the electrical characteristics of the metal ore in this area show a relatively low resistance,and according to its resistivity difference with surrounding rocks,the geometrical structures and apparent resistivity parameters of the low resistivity bodies in the lower section of the survey line are defined,and the electrical anomalies can be identified;(2)faults F1 and F2 may have a good metallogenic environment,so they are recommended for further exploration;(3) low resistance metal ore bodies have good correlation with local small structures or faults,which may play an iconic role for the delineation of key target areas;(4) in the process of using apparent resistivity to define the geometric structures of ore bodies underground,comprehensive analysis integrating the advantages of TE and TM models should be carry out to achieve more reliable inversion results.
