Physiologically, the atria contract first, followed by the ventricles, which is the prerequisite for normal blood circulation. The above phenomenon of atrioventricular sequential contraction results from the characteristically slow conduction of electrical excitation of the atrioventricular node (AVN) between the atria and the ventricles. However, it is not clear what controls the conduction of electrical excitation within AVNs. Here, we find that AVN pacemaker cells (AVNPCs) possess an intact intrinsic GABAergic system, which plays a key role in electrical conduction from the atria to the ventricles. First, along with the discovery of abundant GABA-containing vesicles under the surface membranes of AVNPCs, key elements of the GABAergic system, including GABA metabolic enzymes, GABA receptors, and GABA transporters, were identified in AVNPCs. Second, GABA synchronously elicited GABA-gated currents in AVNPCs, which significantly weakened the excitability of AVNPCs. Third, the key molecular elements of the GABAergic system markedly modulated the conductivity of electrical excitation in the AVN. Fourth, GABAA receptor deficiency in AVNPCs accelerated atrioventricular conduction, which impaired the AVN’s protective potential against rapid ventricular frequency responses, increased susceptibility to lethal ventricular arrhythmias, and decreased the cardiac contractile function. Finally, interventions targeting the GABAergic system effectively prevented the occurrence and development of atrioventricular block. In summary, the endogenous GABAergic system in AVNPCs determines the slow conduction of electrical excitation within AVNs, thereby ensuring sequential atrioventricular contraction. The endogenous GABAergic system shows promise as a novel intervention target for cardiac arrhythmias.
{"title":"A GABAergic system in atrioventricular node pacemaker cells controls electrical conduction between the atria and ventricles","authors":"Dandan Liang, Liping Zhou, Huixing Zhou, Fulei Zhang, Guojian Fang, Junwei Leng, Yahan Wu, Yuemei Zhang, Anqi Yang, Yi Liu, Yi-Han Chen","doi":"10.1038/s41422-024-00980-x","DOIUrl":"10.1038/s41422-024-00980-x","url":null,"abstract":"Physiologically, the atria contract first, followed by the ventricles, which is the prerequisite for normal blood circulation. The above phenomenon of atrioventricular sequential contraction results from the characteristically slow conduction of electrical excitation of the atrioventricular node (AVN) between the atria and the ventricles. However, it is not clear what controls the conduction of electrical excitation within AVNs. Here, we find that AVN pacemaker cells (AVNPCs) possess an intact intrinsic GABAergic system, which plays a key role in electrical conduction from the atria to the ventricles. First, along with the discovery of abundant GABA-containing vesicles under the surface membranes of AVNPCs, key elements of the GABAergic system, including GABA metabolic enzymes, GABA receptors, and GABA transporters, were identified in AVNPCs. Second, GABA synchronously elicited GABA-gated currents in AVNPCs, which significantly weakened the excitability of AVNPCs. Third, the key molecular elements of the GABAergic system markedly modulated the conductivity of electrical excitation in the AVN. Fourth, GABAA receptor deficiency in AVNPCs accelerated atrioventricular conduction, which impaired the AVN’s protective potential against rapid ventricular frequency responses, increased susceptibility to lethal ventricular arrhythmias, and decreased the cardiac contractile function. Finally, interventions targeting the GABAergic system effectively prevented the occurrence and development of atrioventricular block. In summary, the endogenous GABAergic system in AVNPCs determines the slow conduction of electrical excitation within AVNs, thereby ensuring sequential atrioventricular contraction. The endogenous GABAergic system shows promise as a novel intervention target for cardiac arrhythmias.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"34 8","pages":"556-571"},"PeriodicalIF":28.1,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-024-00980-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141287092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-04DOI: 10.1038/s41422-024-00981-w
Qiyin An, Yong Wang, Zhenhua Tian, Jie Han, Jinyue Li, Fumeng Liao, Feiyang Yu, Haiyan Zhao, Yancheng Wen, Heng Zhang, Zengqin Deng
Coupling distinct enzymatic effectors emerges as an efficient strategy for defense against phage infection in bacterial immune responses, such as the widely studied nuclease and cyclase activities in the type III CRISPR-Cas system. However, concerted enzymatic activities in other bacterial defense systems are poorly understood. Here, we biochemically and structurally characterize a two-component defense system DUF4297–HerA, demonstrating that DUF4297–HerA confers resistance against phage infection by cooperatively cleaving dsDNA and hydrolyzing ATP. DUF4297 alone forms a dimer, and HerA alone exists as a nonplanar split spiral hexamer, both of which exhibit extremely low enzymatic activity. Interestingly, DUF4297 and HerA assemble into an approximately 1 MDa supramolecular complex, where two layers of DUF4297 (6 DUF4297 molecules per layer) linked via inter-layer dimerization of neighboring DUF4297 molecules are stacked on top of the HerA hexamer. Importantly, the complex assembly promotes dimerization of DUF4297 molecules in the upper layer and enables a transition of HerA from a nonplanar hexamer to a planar hexamer, thus activating their respective enzymatic activities to abrogate phage infection. Together, our findings not only characterize a novel dual-enzyme anti-phage defense system, but also reveal a unique activation mechanism by cooperative complex assembly in bacterial immunity.
{"title":"Molecular and structural basis of an ATPase-nuclease dual-enzyme anti-phage defense complex","authors":"Qiyin An, Yong Wang, Zhenhua Tian, Jie Han, Jinyue Li, Fumeng Liao, Feiyang Yu, Haiyan Zhao, Yancheng Wen, Heng Zhang, Zengqin Deng","doi":"10.1038/s41422-024-00981-w","DOIUrl":"10.1038/s41422-024-00981-w","url":null,"abstract":"Coupling distinct enzymatic effectors emerges as an efficient strategy for defense against phage infection in bacterial immune responses, such as the widely studied nuclease and cyclase activities in the type III CRISPR-Cas system. However, concerted enzymatic activities in other bacterial defense systems are poorly understood. Here, we biochemically and structurally characterize a two-component defense system DUF4297–HerA, demonstrating that DUF4297–HerA confers resistance against phage infection by cooperatively cleaving dsDNA and hydrolyzing ATP. DUF4297 alone forms a dimer, and HerA alone exists as a nonplanar split spiral hexamer, both of which exhibit extremely low enzymatic activity. Interestingly, DUF4297 and HerA assemble into an approximately 1 MDa supramolecular complex, where two layers of DUF4297 (6 DUF4297 molecules per layer) linked via inter-layer dimerization of neighboring DUF4297 molecules are stacked on top of the HerA hexamer. Importantly, the complex assembly promotes dimerization of DUF4297 molecules in the upper layer and enables a transition of HerA from a nonplanar hexamer to a planar hexamer, thus activating their respective enzymatic activities to abrogate phage infection. Together, our findings not only characterize a novel dual-enzyme anti-phage defense system, but also reveal a unique activation mechanism by cooperative complex assembly in bacterial immunity.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"34 8","pages":"545-555"},"PeriodicalIF":28.1,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11291478/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141247608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-04DOI: 10.1038/s41422-024-00984-7
Changyao Li, Heng Liu, Jingru Li, Xinheng He, Haoran Zhu, Wei Fu, H. Eric Xu
{"title":"Molecular basis of ligand recognition and activation of the human succinate receptor SUCR1","authors":"Changyao Li, Heng Liu, Jingru Li, Xinheng He, Haoran Zhu, Wei Fu, H. Eric Xu","doi":"10.1038/s41422-024-00984-7","DOIUrl":"10.1038/s41422-024-00984-7","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"34 8","pages":"594-596"},"PeriodicalIF":28.1,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141247627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-31DOI: 10.1038/s41422-024-00983-8
Haopeng Wang, Shizhen Qiu, Mohamad Mohty
{"title":"All-in-one Hangzhou Protocol: killing four birds with one stone","authors":"Haopeng Wang, Shizhen Qiu, Mohamad Mohty","doi":"10.1038/s41422-024-00983-8","DOIUrl":"10.1038/s41422-024-00983-8","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"34 10","pages":"1-2"},"PeriodicalIF":28.1,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-024-00983-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141182864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bidirectional transcription of mammalian mitochondrial DNA generates overlapping transcripts that are capable of forming double-stranded RNA (dsRNA) structures. Release of mitochondrial dsRNA into the cytosol activates the dsRNA-sensing immune signaling, which is a defense mechanism against microbial and viral attack and possibly cancer, but could cause autoimmune diseases when unchecked. A better understanding of the process is vital in therapeutic application of this defense mechanism and treatment of cognate human diseases. In addition to exporting dsRNAs, mitochondria also export and import a variety of non-coding RNAs. However, little is known about how these RNAs are transported across mitochondrial membranes. Here we provide direct evidence showing that adenine nucleotide translocase-2 (ANT2) functions as a mammalian RNA translocon in the mitochondrial inner membrane, independent of its ADP/ATP translocase activity. We also show that mitochondrial dsRNA efflux through ANT2 triggers innate immunity. Inhibiting this process alleviates inflammation in vivo, providing a potential therapeutic approach for treating autoimmune diseases.
{"title":"ANT2 functions as a translocon for mitochondrial cross-membrane translocation of RNAs","authors":"Pengcheng Wang, Lixiao Zhang, Siyi Chen, Renjian Li, Peipei Liu, Xiang Li, Hongdi Luo, Yujia Huo, Zhirong Zhang, Yiqi Cai, Xu Liu, Jinliang Huang, Guangkeng Zhou, Zhe Sun, Shanwei Ding, Jiahao Shi, Zizhuo Zhou, Ruoxi Yuan, Liang Liu, Sipeng Wu, Geng Wang","doi":"10.1038/s41422-024-00978-5","DOIUrl":"10.1038/s41422-024-00978-5","url":null,"abstract":"Bidirectional transcription of mammalian mitochondrial DNA generates overlapping transcripts that are capable of forming double-stranded RNA (dsRNA) structures. Release of mitochondrial dsRNA into the cytosol activates the dsRNA-sensing immune signaling, which is a defense mechanism against microbial and viral attack and possibly cancer, but could cause autoimmune diseases when unchecked. A better understanding of the process is vital in therapeutic application of this defense mechanism and treatment of cognate human diseases. In addition to exporting dsRNAs, mitochondria also export and import a variety of non-coding RNAs. However, little is known about how these RNAs are transported across mitochondrial membranes. Here we provide direct evidence showing that adenine nucleotide translocase-2 (ANT2) functions as a mammalian RNA translocon in the mitochondrial inner membrane, independent of its ADP/ATP translocase activity. We also show that mitochondrial dsRNA efflux through ANT2 triggers innate immunity. Inhibiting this process alleviates inflammation in vivo, providing a potential therapeutic approach for treating autoimmune diseases.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"34 7","pages":"504-521"},"PeriodicalIF":28.1,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141174944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-27DOI: 10.1038/s41422-024-00977-6
Carlos López-Otín, Andrea B. Maier, Guido Kroemer
{"title":"Gerogenes and gerosuppression: the pillars of precision geromedicine","authors":"Carlos López-Otín, Andrea B. Maier, Guido Kroemer","doi":"10.1038/s41422-024-00977-6","DOIUrl":"10.1038/s41422-024-00977-6","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"34 7","pages":"463-466"},"PeriodicalIF":28.1,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11217286/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141156907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-23DOI: 10.1038/s41422-024-00979-4
Pavel Hanč, Ulrich H. von Andrian
{"title":"No pain, no gain — how nociceptors orchestrate tissue repair","authors":"Pavel Hanč, Ulrich H. von Andrian","doi":"10.1038/s41422-024-00979-4","DOIUrl":"10.1038/s41422-024-00979-4","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"34 10","pages":"673-674"},"PeriodicalIF":28.1,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-024-00979-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141087185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-22DOI: 10.1038/s41422-024-00971-y
Tae-Yoon Park, Jeha Jeon, Young Cha, Kwang-Soo Kim
Parkinson’s disease (PD) stands as the second most common neurodegenerative disorder after Alzheimer’s disease, and its prevalence continues to rise with the aging global population. Central to the pathophysiology of PD is the specific degeneration of midbrain dopamine neurons (mDANs) in the substantia nigra. Consequently, cell replacement therapy (CRT) has emerged as a promising treatment approach, initially supported by various open-label clinical studies employing fetal ventral mesencephalic (fVM) cells. Despite the initial favorable results, fVM cell therapy has intrinsic and logistical limitations that hinder its transition to a standard treatment for PD. Recent efforts in the field of cell therapy have shifted its focus towards the utilization of human pluripotent stem cells, including human embryonic stem cells and induced pluripotent stem cells, to surmount existing challenges. However, regardless of the transplantable cell sources (e.g., xenogeneic, allogeneic, or autologous), the poor and variable survival of implanted dopamine cells remains a major obstacle. Emerging evidence highlights the pivotal role of host immune responses following transplantation in influencing the survival of implanted mDANs, underscoring an important area for further research. In this comprehensive review, building upon insights derived from previous fVM transplantation studies, we delve into the functional ramifications of host immune responses on the survival and efficacy of grafted dopamine cells. Furthermore, we explore potential strategic approaches to modulate the host immune response, ultimately aiming for optimal outcomes in future clinical applications of CRT for PD.
{"title":"Past, present, and future of cell replacement therapy for parkinson’s disease: a novel emphasis on host immune responses","authors":"Tae-Yoon Park, Jeha Jeon, Young Cha, Kwang-Soo Kim","doi":"10.1038/s41422-024-00971-y","DOIUrl":"10.1038/s41422-024-00971-y","url":null,"abstract":"Parkinson’s disease (PD) stands as the second most common neurodegenerative disorder after Alzheimer’s disease, and its prevalence continues to rise with the aging global population. Central to the pathophysiology of PD is the specific degeneration of midbrain dopamine neurons (mDANs) in the substantia nigra. Consequently, cell replacement therapy (CRT) has emerged as a promising treatment approach, initially supported by various open-label clinical studies employing fetal ventral mesencephalic (fVM) cells. Despite the initial favorable results, fVM cell therapy has intrinsic and logistical limitations that hinder its transition to a standard treatment for PD. Recent efforts in the field of cell therapy have shifted its focus towards the utilization of human pluripotent stem cells, including human embryonic stem cells and induced pluripotent stem cells, to surmount existing challenges. However, regardless of the transplantable cell sources (e.g., xenogeneic, allogeneic, or autologous), the poor and variable survival of implanted dopamine cells remains a major obstacle. Emerging evidence highlights the pivotal role of host immune responses following transplantation in influencing the survival of implanted mDANs, underscoring an important area for further research. In this comprehensive review, building upon insights derived from previous fVM transplantation studies, we delve into the functional ramifications of host immune responses on the survival and efficacy of grafted dopamine cells. Furthermore, we explore potential strategic approaches to modulate the host immune response, ultimately aiming for optimal outcomes in future clinical applications of CRT for PD.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"34 7","pages":"479-492"},"PeriodicalIF":28.1,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11217403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141079663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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