Article
Cardiac & Cardiovascular Systems
Katalin Marta, Prottoy Hasan, Macarena Rodriguez-Prados, Melanie Paillard, Gyorgy Hajnoczky
Summary: Mitochondrial Ca2+ uptake is crucial for meeting the fluctuating energy demands of cells and is mediated by the Ca2+ uniporter. Pharmacological manipulation of mtCU is key to understanding its physiological significance, but specific inhibitors have not been identified. Success in developing small molecule mtCU inhibitors is expected to have clinical impact in various diseases.
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
(2021)
Article
Pharmacology & Pharmacy
Zhiwang Zhang, Zupeng Luo, Lin Yu, Yang Xiao, Siqi Liu, Zhier ALuo, Zeqiang Ma, Liang Huang, Lianggui Xiao, Mengting Jia, Ziyi Song, Haojie Zhang, Yixing Li, Lei Zhou
Summary: This study investigates the role of mitochondrial calcium uniporter (MCU) in hepatic steatosis induced by high-fat diet (HFD). The results show that inhibition of liver MCU can prevent HFD-induced liver steatosis. The study also reveals that HFD enlarges the mitochondria-associated membranes (MAM) and disrupts mitochondrial calcium homeostasis, leading to liver fat deposition. Inhibition of MAM and MCU can alleviate HFD-induced hepatic steatosis. MCU inhibitors can block MCU channels and reduce mitochondrial calcium levels, providing a potential drug target for the treatment of hepatic steatosis.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Jiho Yoo
Summary: Mitochondria, organelles responsible for various cellular functions, uptake Ca2+ ions through the MCU holo-complex. The protein structure of the MCU holo-complex has recently been identified, providing insights into the uptake and regulation mechanisms.
Article
Biochemistry & Molecular Biology
Ioana Stejerean-Todoran, Katharina Zimmermann, Christine S. Gibhardt, Adina Vultur, Christian Ickes, Batool Shannan, Zurine Bonilla del Rio, Anna Wolling, Sabrina Cappello, Hsu-Min Sung, Magdalena Shumanska, Xin Zhang, Maithily Nanadikar, Muhammad U. Latif, Anna Wittek, Felix Lange, Andrea Waters, Patricia Brafford, Jorg Wilting, Henning Urlaub, Dorthe M. Katschinski, Peter Rehling, Christof Lenz, Stefan Jakobs, Volker Ellenrieder, Alexander Roesch, Michael P. Schon, Meenhard Herlyn, Hedwig Stanisz, Ivan Bogeski
Summary: MCUA expression correlates with melanoma patient survival and MCUA knockdown suppresses melanoma cell growth and stimulates migration and invasion. Knockdown of MCUA reduces tumor volumes but promotes lung metastases.
Review
Cell Biology
Grant C. C. Walters, Yuriy M. M. Usachev
Summary: Mitochondria play essential roles in cellular function, including ATP synthesis, reactive oxygen species production, calcium buffering, and apoptotic signaling. In neurons, calcium buffering is particularly important for regulating various calcium-dependent functions. Recent discoveries of molecular components involved in mitochondrial calcium transport have shed light on the roles of mitochondrial calcium regulation in neuronal function and its implications in neurological diseases. This review discusses the multiple roles of mitochondrial calcium uptake and release mechanisms in normal neuronal function and provides insight into the calcium-dependent mechanisms underlying mitochondrial dysfunction in neurological diseases. The targeting of calcium uptake and release mechanisms could potentially lead to novel therapeutic strategies for these diseases.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Linlin Zhang, Jingyi Qi, Xu Zhang, Xiya Zhao, Peng An, Yongting Luo, Junjie Luo
Summary: Mitochondria are essential for cellular energy metabolism and the generation of oxygen free radicals, and also play a crucial role in cell death. Ca2+ acts as a messenger for cell proliferation and death, and is involved in the energy metabolism, physiology, and pathology of mitochondria.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Biochemistry & Molecular Biology
Paulina Sander, Thomas Gudermann, Johann Schredelseker
Summary: Research on mitochondrial Ca2+ uptake mainly focuses on the function, regulation, and localization of the mitochondrial calcium uniporter complex (MCUC), while also investigating the role of the outer mitochondrial membrane channels in regulating this process.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Ahmed Rohaim, Bram J. A. Vermeulen, Jing Li, Felix Kummerer, Federico Napoli, Lydia Blachowicz, Joao Medeiros-Silva, Benoit Roux, Markus Weingarth
Summary: C-type inactivation is physiologically important in Kv channels, but its structural basis is not fully understood. Previous knowledge about C-type inactivation is mainly derived from the bacterial KcsA channel, which has a different molecular environment compared to Kv channels. This study investigates a KcsA mutant that resembles Kv channels and reveals a distinct mechanism for C-type inactivation.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Adam Lewis, Vilius Kurauskas, Marco Tonelli, Katherine Henzler-Wildman
Summary: The selectivity filter (SF) in NaK is dynamic, with structural differences between Na+ and K+-bound states, determining efficient conduction of ions. The SF structure communicates with the pore-lining helices, supporting multiple conformations involved in non-selective conduction. Allosteric coupling between the SF and pore-lining helices is demonstrated, similar to that in K+-selective channels, indicating a general model for ion channel function.
NATURE COMMUNICATIONS
(2021)
Article
Multidisciplinary Sciences
Zhao Yang, Xue Zhang, Shiwei Ye, Jingtao Zheng, Xiaowei Huang, Fang Yu, Zhenguo Chen, Shiqing Cai, Peng Zhang
Summary: Chloride channels (CLCs) are regulated by nucleotides and phospholipids. The cryo-EM structures of Arabidopsis thaliana CLCa (AtCLCa) bound with NO3- and Cl- reveal the regulatory mechanisms of nucleotides and phospholipids. This study provides new insights for the future study of CLCs.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Yue Sun, Yan-Ming Yang, Yu-Yu Hu, Lan Ouyang, Zheng-Hua Sun, Xing-Feng Yin, Nan Li, Qing-Yu He, Yang Wang
Summary: This study reveals the impact of SIRT1 inhibition on SIRT1-dependent acetylation in colorectal cancer cells using quantitative acetyl-proteomics. Inhibition of SIRT1 increases protein acetylation in mitochondria, leading to mitochondrial dysfunction and cell apoptosis.
Article
Chemistry, Physical
Yukina Suzuki, Keisuke Hirata, James M. Lisy, Shun-ichi Ishiuchi, Masaaki Fujii
Summary: This study characterizes the selectivity of K+ channels at a molecular level by investigating hydrated alkali metal complexes of a model peptide. The differences in spectral features between permeable and non-permeable ions are revealed. The impact of hydration on K+ channels is also discussed.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2022)
Article
Chemistry, Physical
Dezso Boda, Dirk Gillespie
Summary: This paper proposes a modified Grand Canonical Monte Carlo (GCMC) method for handling Donnan equilibrium, which achieves equilibrium between two implicit-solvent bath electrolytes with different dielectric constants. By deducting the solvation energy and electrical potential difference between the two baths from the chemical potential of the reservoir, the resulting chemical potential is used in the system simulation called Donnan GCMC. This simulation provides the distribution of ions between the two baths from a single run, eliminating the need for a numerical procedure requiring multiple GCMC runs.
JOURNAL OF MOLECULAR LIQUIDS
(2023)
Review
Physiology
Joanne F. Garbincius, John W. Elrod
Summary: The uptake and extrusion of calcium into and from the mitochondrial matrix have significant effects on cellular metabolism, signaling, and survival. Disruption of mitochondrial calcium cycling is associated with various diseases and inherited neuromuscular disorders. This review provides an overview of the molecular machinery involved in calcium flux across the inner mitochondrial membrane and discusses the physiological implications and potential therapeutic interventions for diseases characterized by aberrant calcium handling. Critical unanswered questions regarding the biology of calcium flux are also highlighted.
PHYSIOLOGICAL REVIEWS
(2022)
Article
Biochemistry & Molecular Biology
Atsushi Higashitani, Mika Teranishi, Yui Nakagawa, Yukou Itoh, Surabhi Sudevan, Nathaniel J. Szewczyk, Yukihiko Kubota, Takaaki Abe, Takeshi Kobayashi
Summary: Sarcopenia, a syndrome characterized by age-related decline in skeletal muscle mass and strength, can be improved by suppressing mitochondrial calcium uniporter (MCU)-mediated Ca2+ influx into mitochondria. In this study, researchers found that aged muscle cells showed elevated resting mitochondrial Ca2+ levels and increased mitophagy, and suppressing MCU function improved movement in muscular dystrophy. These results suggest that elevated resting mitochondrial Ca2+ levels contribute to muscle decline with age and modulation of MCU activity could be an effective pharmacological target for muscle loss.
Article
Biochemistry & Molecular Biology
Tianshu Xiao, Gary Frey, Qingshan Fu, Christy L. Lavine, David A. Scott, Michael S. Seaman, James J. Chou, Bing Chen
NATURE CHEMICAL BIOLOGY
(2020)
Article
Multidisciplinary Sciences
Alessandro Piai, Qingshan Fu, Yongfei Cai, Fadi Ghantous, Tianshu Xiao, Md Munan Shaik, Hanqin Peng, Sophia Rits-Volloch, Wen Chen, Michael S. Seaman, Bing Chen, James J. Chou
NATURE COMMUNICATIONS
(2020)
Article
Chemistry, Multidisciplinary
Yuan Yuan, Chan Cao, Maorong Wen, Min Li, Ying Dong, Lijie Wu, Jian Wu, Tanxing Cui, Dianfan Li, James J. Chou, Bo OuYang
Article
Cell Biology
Linlin Zhao, Qingshan Fu, Liqiang Pan, Alessandro Piai, James J. Chou
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2020)
Article
Biochemistry & Molecular Biology
Shukun Wei, Xiaoyou Hu, Lingyu Du, Linlin Zhao, Hongjuan Xue, Chaolun Liu, James J. Chou, Jin Zhong, Yimin Tong, Shuqing Wang, Bo OuYang
Summary: Novel p7 inhibitors with amantadine scaffold were screened and two best inhibitors were confirmed. Molecular dynamics simulation and molecular docking analysis revealed that hydrophobic interactions are the dominant forces for the efficacy of inhibitors.
Article
Chemistry, Multidisciplinary
Alessandro Piai, Qingshan Fu, Amanda K. Sharp, Beatrice Bighi, Anne M. Brown, James J. Chou
Summary: This study determined the structure of the cytoplasmic tail (CT) of HIV-1 envelope glycoprotein through NMR, and derived a model of the membrane-interacting region, showcasing stability in a viral membrane and compensation for lipid exclusion by the KS-LLP2 region through molecular dynamics simulations.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Biochemistry & Molecular Biology
Fujiao Lv, Fei Qi, Zhi Zhang, Maorong Wen, Justin Kale, Alessandro Piai, Lingyu Du, Shuqing Wang, Liujuan Zhou, Yaqing Yang, Bin Wu, Zhijun Liu, Juan Rosario, Justin Pogmore, James J. Chou, David W. Andrews, Jialing Lin, Bo OuYang
Summary: Bax proteins form pores in the mitochondrial outer membrane to initiate apoptosis. The high-resolution structure of the Bax core region revealed a dimer with specific surface interactions with lipid bilayers, suggesting its role in forming the pore wall during apoptosis. Structural mutations further confirmed the importance of protein-lipid interactions in Bax pore assembly.
Article
Chemistry, Multidisciplinary
Qingshan Fu, James J. Chou
Summary: The study identified the structure of the TMD of the S protein of SARS-CoV-2, revealing it as a transmembrane alpha-helix trimer that spontaneously assembles in the membrane, with a strong hydrophobic core. The research also found that, despite being highly stable, single mutations can completely dissociate this trimer.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Microbiology
Jorge J. Velarde, Alessandro Piai, Ian J. Lichtenstein, Nicola N. Lynskey, James J. Chou, Michael R. Wessels
Summary: NADase and SLO are secreted toxins that play important roles in the pathogenesis of Group A Streptococcus infections. Our study reveals that NADase can bind to human cell surfaces independently of SLO. Structural analysis of the NADase translocation domain suggests that it contains a carbohydrate binding module. NADase and SLO appear to recognize similar glycan structures on the cell surface, which may enhance SLO pore-forming activity during infection. These findings provide new insights into the functional interactions between NADase and SLO during streptococcal infection.
JOURNAL OF BACTERIOLOGY
(2022)
Article
Multidisciplinary Sciences
Xinlei Zhuang, Zhe Wang, Jiansheng Fan, Xuefei Bai, Yingchun Xu, James J. Chou, Tingjun Hou, Shuqing Chen, Liqiang Pan
Summary: Researchers have developed a structure-guided and phage-assisted evolution approach to reverse cetuximab resistance mediated by EGFR mutations, without altering the binding epitope or undermining antibody efficacy.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Multidisciplinary
Liujuan Zhou, Fan Yang, Zhaoshuai Bai, Xiaohui Zhou, Zhihai Zhang, Zhihang Li, Junyuan Gong, Junqi Yu, Liqiang Pan, Chan Cao, James J. Chou
Summary: One challenge in improving clinical outcomes of antibody drug conjugates (ADCs) is overcoming cancer resistance to the antibody and/or drug components of ADCs. In this study, a self-assembled left-handed DNA (L-DNA) oligonucleotide was used to link combinatory single-domain antibodies and toxin payloads for tunable and adaptive delivery of ADCs. The newly constructed ADCs with L-DNA scaffold showed promising properties in vitro and in vivo. This suggests that the L-DNA based modular ADC (MADC) platform is a viable option for generating therapeutic ADCs and expanding the therapeutic window.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Multidisciplinary Sciences
Tiantian Cai, Rachel Lenoir Capello, Xiong Pi, Hao Wu, James J. J. Chou
Summary: Common ? chain cytokine receptors, such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptors, are activated by binding to the common ?c receptor (CD132) and also require direct interactions between the transmembrane domains (TMDs) of both the ?c and interleukin receptors (ILRs) for activation. The same ?c TMD can recognize multiple ILR TMDs with diverse sequences, and the heterodimer structures of ?c TMD bound to IL-7 and IL-9 receptor TMDs reveal a conserved recognition mechanism that allows receptor sharing within the membrane.
Article
Cell Biology
Gang Du, Linlin Zhao, Yumei Zheng, Anissa Belfetmi, Tiantian Cai, Boying Xu, Karen Heyninck, Kim Van Den Heede, Marie-Ange Buyse, Pietro Fontana, Michael Bowman, Lih-Ling Lin, Hao Wu, James Jeiwen Chou
Summary: Members of the TNFRSF can be activated to induce death of cancer cells or stimulate proliferation of immune cells. The self-association structure of the ectodomain of DR5-ECD, a representative member of TNFRSF, has been determined by NMR. The preligand association of DR5 serves an autoinhibitory role and disruption of the preligand cluster can enhance receptor signaling. This mechanism provides a new opportunity for developing agonistic molecules by targeting receptor preligand clustering.
Meeting Abstract
Biophysics
Tianmin Fu, Hao Wu, James Chou
BIOPHYSICAL JOURNAL
(2020)