Copper （Cu） is an important mineral nutrient found in chloroplasts as a cofactor associated with plastocyanin and Cu/Zn superoxide dismutase （Cu/ZnSOD）. Superoxide dismutases are metallo-enzymes found in most oxyg...Copper （Cu） is an important mineral nutrient found in chloroplasts as a cofactor associated with plastocyanin and Cu/Zn superoxide dismutase （Cu/ZnSOD）. Superoxide dismutases are metallo-enzymes found in most oxygenic organisms with proposed roles in reducing oxidative stress. Several recent studies in Arabidopsis have shown that microRNAs and a SQUAMOSA promoter binding protein-like7 （SPL7） transcription factor function to down-regulate the expression of many Cu-proteins, including Cu/ZnSOD in both plastids and the cytosol, during growth on low Cu. Plants contain the Cu Chaperone for SOD （CCS） that delivers Cu to Cu/ZnSODs, and, in Arabidopsis, both cytosolic and plastidic CCS versions are encoded by one gene. In this study, we demonstrate that Arabiclopsis CCS transcript levels are regulated by Cu, mediated by microRNA 398 that was not previously predicted to target CCS. The microRNA target site is conserved in CCS of Oryza sativa. The data suggest that Cu-regulated microRNAs may have more mRNA targets than was previously predicted. A CCS null mutant has no measurable SOD activity in the chloroplast and cytosol, indicating an absolute requirement for CCS. When the CCS null mutant was grown on high Cu media, it lacked both Fe superoxide dismutase （FeSOD） and Cu/ZnSOD activity. However, this did not lead to a visual phenotype and no photosynthetic deficiencies were detected, even after high light stress. These results indicate that Cu/ZnSOD is not a pivotal component of the photosynthetic anti-oxidant system during growth in laboratory conditions.展开更多
Copper is an essential trace element,and plays a vital role in numerous physiological processes within the human body.During normal metabolism,the human body maintains copper homeostasis.Copper deficiency or excess ca...Copper is an essential trace element,and plays a vital role in numerous physiological processes within the human body.During normal metabolism,the human body maintains copper homeostasis.Copper deficiency or excess can adversely affect cellular function.Therefore,copper homeostasis is stringently regulated.Recent studies suggest that copper can trigger a specific form of cell death,namely,cuproptosis,which is triggered by excessive levels of intracellular copper.Cuproptosis induces the aggregation of mitochondrial lipoylated proteins,and the loss of iron-sulfur cluster proteins.In neurodegenerative diseases,the pathogenesis and progression of neurological disorders are linked to copper homeostasis.This review summarizes the advances in copper homeostasis and cuproptosis in the nervous system and neurodegenerative diseases.This offers research perspectives that provide new insights into the targeted treatment of neurodegenerative diseases based on cuproptosis.展开更多
Safe trafficking of iron across the cell membrane is a delicate process that requires specific protein carriers. While many proteins involved in iron uptake by cells are known, only one cellular iron export protein ha...Safe trafficking of iron across the cell membrane is a delicate process that requires specific protein carriers. While many proteins involved in iron uptake by cells are known, only one cellular iron export protein has been identified in mammals: ferroportin(SLC40A1). Ceruloplasmin is a multicopper enzyme endowed with ferroxidase activity that is found as a soluble isoform in plasma or as a membrane-associated isoform in specific cell types. According to the currently accepted view, ferrous iron transported out of the cell by ferroportin would be safely oxidized by ceruloplasmin to facilitate loading on transferrin. Therefore, the ceruloplasminferroportin system represents the main pathway for cellular iron egress and it is responsible for physiological regulation of cellular iron levels. The most recent findings regarding the structural and functional features of ceruloplasmin and ferroportin and their relationship will be described in this review.展开更多
Hepatocellular carcinoma (HCC) has already become a severe health risk and brings a lot of healthcare burden to the world. Apart from traditional HCC treatment strategies (surgery, liver transplantation, etc.), the em...Hepatocellular carcinoma (HCC) has already become a severe health risk and brings a lot of healthcare burden to the world. Apart from traditional HCC treatment strategies (surgery, liver transplantation, etc.), the emergence of immunotherapy targeting the immune microenvironment of HCC has brought new promise to patients with advanced HCC. However, adverse effects like drug resistance still exist. The liver is the main organ for storing copper ions, in copper overload can lead to liver function impairment and even the development of HCC. In recent years, a new mode of cell death has been identified, namely cuproptosis, a mode of programmed cell death that is dependent on copper ions and the tricarboxylic acid (TCA) cycle with mitochondria. Interestingly, a potential relationship between cuproptosis and the development of HCC has been found. Conclusively, this review provides an in-depth discussion of copper homeostasis in humans, the mechanism of cuproptosis, the potential impact of cuproptosis with HCC, and the therapeutic modalities of HCC that target cuproptosis, which provide new insights to promote the development of research targeting cuproptosis in HCC.展开更多
Copper(Cuprum)is an essential trace metal indispensable for the function of numerous enzymatic molecules implicated in cellular metabolism.Emerging evidence has demonstrated the role of copper in angiogenesis and cell...Copper(Cuprum)is an essential trace metal indispensable for the function of numerous enzymatic molecules implicated in cellular metabolism.Emerging evidence has demonstrated the role of copper in angiogenesis and cellular signaling.Moreover,raised copper levels have been detected in hepatocellular carcinoma and other cancers.An inherited or acquired copper imbalance,including inadequately low or excessively high copper levels,as well as inappropriate copper distribution in the body,is implicated in a number of diseases.In addition,a recent groundbreaking study identified a copperinduced type of programmed cell death named cuprotosis,the mechanism of which greatly deferred from that of other known cell death modes.The first part provides an overview of the regulation of copper homeostasis and discusses the underlying mechanisms of cuprotosis.In the second part,the authors focus on the functions of copper in liver diseases and other metabolic disorders,before discussing how this knowledge could contribute to the development of effective targets to treat such diseases.展开更多
基金This work was supported by the United States National Science Foundation （grants NSF-IBN-0418993 and NSF IOS-0847442 to M.P.）.ACKNOWLEDGMENTS We thank Drs Iwona Adamska, Alice Barkan, Daniel Kliebenstein, and Henrik Sheller for generous antibody gifts. We would like to thank Dr Bonnie Bartel for the generous microRNA mutant seed gift. No conflict of interest declared.
文摘Copper （Cu） is an important mineral nutrient found in chloroplasts as a cofactor associated with plastocyanin and Cu/Zn superoxide dismutase （Cu/ZnSOD）. Superoxide dismutases are metallo-enzymes found in most oxygenic organisms with proposed roles in reducing oxidative stress. Several recent studies in Arabidopsis have shown that microRNAs and a SQUAMOSA promoter binding protein-like7 （SPL7） transcription factor function to down-regulate the expression of many Cu-proteins, including Cu/ZnSOD in both plastids and the cytosol, during growth on low Cu. Plants contain the Cu Chaperone for SOD （CCS） that delivers Cu to Cu/ZnSODs, and, in Arabidopsis, both cytosolic and plastidic CCS versions are encoded by one gene. In this study, we demonstrate that Arabiclopsis CCS transcript levels are regulated by Cu, mediated by microRNA 398 that was not previously predicted to target CCS. The microRNA target site is conserved in CCS of Oryza sativa. The data suggest that Cu-regulated microRNAs may have more mRNA targets than was previously predicted. A CCS null mutant has no measurable SOD activity in the chloroplast and cytosol, indicating an absolute requirement for CCS. When the CCS null mutant was grown on high Cu media, it lacked both Fe superoxide dismutase （FeSOD） and Cu/ZnSOD activity. However, this did not lead to a visual phenotype and no photosynthetic deficiencies were detected, even after high light stress. These results indicate that Cu/ZnSOD is not a pivotal component of the photosynthetic anti-oxidant system during growth in laboratory conditions.
基金supported by grants from the National Natural Science Foundation of China(No.81971891,No.82172196 and No.82372507)the Natural Science Foundation of Hunan Province(No.2023JJ40804)the Key Laboratory of Emergency and Trauma of Ministry of Education(Hainan Medical University,No.KLET-202210).
文摘Copper is an essential trace element,and plays a vital role in numerous physiological processes within the human body.During normal metabolism,the human body maintains copper homeostasis.Copper deficiency or excess can adversely affect cellular function.Therefore,copper homeostasis is stringently regulated.Recent studies suggest that copper can trigger a specific form of cell death,namely,cuproptosis,which is triggered by excessive levels of intracellular copper.Cuproptosis induces the aggregation of mitochondrial lipoylated proteins,and the loss of iron-sulfur cluster proteins.In neurodegenerative diseases,the pathogenesis and progression of neurological disorders are linked to copper homeostasis.This review summarizes the advances in copper homeostasis and cuproptosis in the nervous system and neurodegenerative diseases.This offers research perspectives that provide new insights into the targeted treatment of neurodegenerative diseases based on cuproptosis.
文摘Safe trafficking of iron across the cell membrane is a delicate process that requires specific protein carriers. While many proteins involved in iron uptake by cells are known, only one cellular iron export protein has been identified in mammals: ferroportin(SLC40A1). Ceruloplasmin is a multicopper enzyme endowed with ferroxidase activity that is found as a soluble isoform in plasma or as a membrane-associated isoform in specific cell types. According to the currently accepted view, ferrous iron transported out of the cell by ferroportin would be safely oxidized by ceruloplasmin to facilitate loading on transferrin. Therefore, the ceruloplasminferroportin system represents the main pathway for cellular iron egress and it is responsible for physiological regulation of cellular iron levels. The most recent findings regarding the structural and functional features of ceruloplasmin and ferroportin and their relationship will be described in this review.
文摘Hepatocellular carcinoma (HCC) has already become a severe health risk and brings a lot of healthcare burden to the world. Apart from traditional HCC treatment strategies (surgery, liver transplantation, etc.), the emergence of immunotherapy targeting the immune microenvironment of HCC has brought new promise to patients with advanced HCC. However, adverse effects like drug resistance still exist. The liver is the main organ for storing copper ions, in copper overload can lead to liver function impairment and even the development of HCC. In recent years, a new mode of cell death has been identified, namely cuproptosis, a mode of programmed cell death that is dependent on copper ions and the tricarboxylic acid (TCA) cycle with mitochondria. Interestingly, a potential relationship between cuproptosis and the development of HCC has been found. Conclusively, this review provides an in-depth discussion of copper homeostasis in humans, the mechanism of cuproptosis, the potential impact of cuproptosis with HCC, and the therapeutic modalities of HCC that target cuproptosis, which provide new insights to promote the development of research targeting cuproptosis in HCC.
基金supported by the National Natural Science Foundation of China(No.82170696)Shanghai Municipal Hospital New Frontier Technology Joint Research Project(No.SHDC12022104)Shanghai Tongji Hospital Clinical Cultivation Project[No.ITJ(ZD)2201]。
基金Talent Development Plan for Beijing High-level Public Health Technical Personnel Project,Grant/Award Number:2022-2-014。
文摘Copper(Cuprum)is an essential trace metal indispensable for the function of numerous enzymatic molecules implicated in cellular metabolism.Emerging evidence has demonstrated the role of copper in angiogenesis and cellular signaling.Moreover,raised copper levels have been detected in hepatocellular carcinoma and other cancers.An inherited or acquired copper imbalance,including inadequately low or excessively high copper levels,as well as inappropriate copper distribution in the body,is implicated in a number of diseases.In addition,a recent groundbreaking study identified a copperinduced type of programmed cell death named cuprotosis,the mechanism of which greatly deferred from that of other known cell death modes.The first part provides an overview of the regulation of copper homeostasis and discusses the underlying mechanisms of cuprotosis.In the second part,the authors focus on the functions of copper in liver diseases and other metabolic disorders,before discussing how this knowledge could contribute to the development of effective targets to treat such diseases.
