Article
Chemistry, Medicinal
Xiaoguang Liu, Aimee A. Flores, Lisa Situ, Wen Gu, Hui Ding, Heather R. Christofk, William E. Lowry, Michael E. Jung
Summary: The study reports the synthesis and evaluation of novel UK-5099 analogues for potential treatment of hair loss, with certain compounds showing significant MPC inhibition activity and expanding chemical space for drug design. Some analogues were found to promote hair growth in mice when tested through topical treatment.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Immunology
Lih-Chyang Chen, Yu-Jen Chen, Hsin-An Lin, Wu-Chien Chien, Kuen-Jou Tsai, Chi-Hsiang Chung, Jui-Yang Wang, Chien-Chou Chen, Nan-Shih Liao, Chieh-Tien Shih, Yi-Ying Lin, Chi-Ning Huang, David M. Ojcius, Kuo-Yang Huang, Hsin-Chung Lin
Summary: Glycolysis regulated NLRP3 inflammasome activation and the development of autoinflammatory diseases. Inhibition of mitochondrial pyruvate carrier increased NLRP3 inflammasome activation and the risk of gout in diabetic individuals.
Article
Pharmacology & Pharmacy
Mohamed Touaibia, Patrick-Denis St-Coeur, Patrick Duff, Diene Codou Faye, Nicolas Pichaud
Summary: A series of thiazolidinediones were synthesized and studied for their effects on Drosophila melanogaster mitochondrial respiration. Compounds like 5-benzylidenethiazolidine-2,4-diones exhibited strong inhibitory capacity compared to other analogs, showing potential as potent mitochondrial pyruvate carrier inhibitors similar to UK5099. An analog, 5-benzylidenethiazolidine-2,4-dione 3, demonstrated positive effects on fruit fly survival and longevity, reversing the effects of a high fat diet and suggesting in vivo inhibition of MPC at the mitochondrial level.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Kyle S. McCommis, Brian N. Finck
Summary: Pyruvate is a crucial metabolic product that needs to be transported to the mitochondrial matrix for energy utilization or to become the building block of new biomolecules. The mitochondrial pyruvate carrier (MPC) has emerged as a target for therapeutic intervention in diseases related to altered mitochondrial and intermediary metabolism. In this review, the role of MPC and related metabolic pathways in the liver in regulating energy metabolism and the current state of targeting this pathway to treat liver diseases are discussed. Inhibiting MPC in hepatocytes and other liver cells has shown beneficial effects in treating type 2 diabetes and nonalcoholic steatohepatitis, although there are still gaps in our understanding of the pleiotropic effects of MPC inhibition.
Article
Microbiology
Raquel S. Negreiros, Noelia Lander, Miguel A. Chiurillo, Anibal E. Vercesi, Roberto Docampo
Summary: Pyruvate, the end product of glycolysis, is transported into the mitochondria through the mitochondrial pyruvate carriers MPC1 and MPC2. Knockout of MPC1 and MPC2 in Trypanosoma cruzi affects pyruvate-driven respiration, host cell invasion, and intracellular replication of amastigotes.
Article
Biochemistry & Molecular Biology
Xia Fang, Pei Zhao, Shaoyong Gao, Dongmei Liu, Song Zhang, Mengtian Shan, Yuanyuan Wang, Joerg Herrmann, Qiang Li, Feilong Wang
Summary: Tumor cell-derived lactate has been identified as the main factor in the polarization of tumor-associated macrophages (TAMs). Previous studies have highlighted the importance of mitochondrial pyruvate carrier (MPC)-mediated transport in TAMs polarization. However, our genetic depletion study demonstrated that MPC is not necessary for lactate-induced macrophages polarization or tumor growth.It also had no impact on the stabilization of hypoxia-inducible factor 1 alpha (HIF-1 alpha) and histone lactylation, which are both crucial for TAMs polarization. This suggests that lactate itself, rather than its downstream metabolites, is responsible for TAMs polarization.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
Article
Multidisciplinary Sciences
Karla T. Falcon, Kristin E. N. Watt, Soma Dash, Ruonan Zhao, Daisuke Sakai, Emma L. Moore, Sharien Fitriasari, Melissa Childers, Mihaela E. Sardiu, Selene Swanson, Dai Tsuchiya, Jay Unruh, George Bugarinovic, Lin Li, Rita Shiang, Annita Achilleos, Jill Dixon, Michael J. Dixon, Paul A. Trainor
Summary: This study investigates the importance of ribosomal RNA (rRNA) transcription in craniofacial development and the implications of disruptions in this process. The researchers discovered that high expression of Pol I subunits in neuroepithelium and neural crest cells (NCCs) sustains elevated rRNA transcription, supporting the high levels of protein translation in these cells. However, disruptions in rRNA synthesis in NCCs can lead to p53 protein accumulation, NCC apoptosis, and craniofacial anomalies. Compound mutations in Pol I subunits further exacerbate these anomalies. Mechanistically, diminished rRNA synthesis causes an imbalance between rRNA and ribosomal proteins, affecting the binding of these proteins with Mdm2 and p53. This study highlights the critical role of rRNA transcription in craniofacial development and its specific sensitivities to disruptions in certain congenital craniofacial disorders.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Endocrinology & Metabolism
Sotiria Tavoulari, Tom J. J. Schirris, Vasiliki Mavridou, Chancievan Thangaratnarajah, Martin S. King, Daniel T. D. Jones, Shujing Ding, Ian M. Fearnley, Edmund R. S. Kunji
Summary: This study characterized the human mitochondrial pyruvate carrier (MPC) protein and identified the chemical features necessary for high-affinity inhibition. It found that three hydrogen bond acceptors followed by an aromatic ring are shared characteristics of all inhibitors and represent the minimal requirement for high potency. The study also discovered 14 new MPC inhibitors, with one compound outperforming a known inhibitor by tenfold.
MOLECULAR METABOLISM
(2022)
Article
Biochemistry & Molecular Biology
Lamees Hegazy, Lauren E. Gill, Kelly D. Pyles, Christopher Kaiho, Sophia Kchouk, Brian N. Finck, Kyle S. McCommis, Bahaa Elgendy
Summary: This study reveals the structure-function relationships of the mitochondrial pyruvate carrier (MPC) complex using homology modeling and mutagenesis experiments. Based on this, a pharmacophore model is developed and a virtual screen identifies five new drug-like MPC inhibitors.
Article
Biology
Takeshi Yoneshiro, Naoya Kataoka, Jacquelyn M. Walejko, Kenji Ikeda, Zachary Brown, Momoko Yoneshiro, Scott B. Crown, Tsuyoshi Osawa, Juro Sakai, Robert W. McGarrah, Phillip J. White, Kazuhiro Nakamura, Shingo Kajimura
Summary: This study investigates the role of mitochondrial BCAA carrier in regulating BCAA catabolism and adaptive response to fever, highlighting the significant enhancement of mitochondrial BCAA oxidation during fever and the essential role of MBC in BCAA deamination and thermogenesis.
Article
Biotechnology & Applied Microbiology
Juhong Chen, Wenzhao Xu, Zi Wang, Li Tian, Weidong Liu, Ang Ren, Rui Liu, Jing Zhu, Liang Shi
Summary: Mitochondrial pyruvate carriers play a crucial role in regulating the biosynthesis of ganoderic acid in Ganoderma lucidum.
APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
(2023)
Article
Medicine, Research & Experimental
Yue Liu, Yuan Yuan, Yi Yan, Ruyue Wang, Zhaohui Wang, Xiao Liu, Ying Zhang, Jianyu Hua, Yue Wang, Li Zhao
Summary: This research aims to investigate the impact of mitochondrial dysfunction on cerebral ischemia and explore the role of mitochondrial pyruvate carrier 1 (MPC1) in this process. The study demonstrates that MPC1 can exert a neuroprotective effect on cerebral ischemia by attenuating oxidative stress, mitochondrial dysfunction, calcium overload, and autophagy. The findings suggest that MPC1-related genes identified through RNA-seq may serve as a novel therapeutic target for cerebral ischemia.
Review
Physiology
Sotiria Tavoulari, Maximilian Sichrovsky, Edmund R. S. Kunji
Summary: Mitochondrial pyruvate carrier (MPC) plays a crucial role in connecting cytosolic and mitochondrial metabolism by transporting pyruvate into the mitochondrial matrix. Due to its importance, MPC has been proposed as a potential target for various diseases. However, the knowledge about its structure and mechanism is limited. This article provides critical insights into the composition, structure, and function of MPC, and summarizes the different classes of small molecule inhibitors and their potential in therapeutics.
Article
Biology
Andres De la Rossa, Marine H. Laporte, Simone Astori, Thomas Marissal, Sylvie Montessuit, Preethi Sheshadri, Eva Ramos-Fernandez, Pablo Mendez, Abbas Khani, Charles Quairiaux, Eric B. Taylor, Jared Rutter, Jose Manuel Nunes, Alan Carleton, Michael R. Duchen, Carmen Sandi, Jean-Claude Martinou
Summary: Neuronal excitation relies on ATP from oxidative phosphorylation, and deficient oxidative phosphorylation can lead to hyperexcitability in neurons. Inhibiting GABA activity in mice with deficient mitochondrial pyruvate carrier (MPC) led to seizures and death, but providing ketone bodies restored energy and attenuated seizures. These findings provide insights into epilepsy and other neuropathologies associated with energy deficits.
Article
Endocrinology & Metabolism
Huan Xu, Zhixiao Liu, Dajun Gao, Peizhang Li, Yanting Shen, Yi Sun, Lingfan Xu, Nan Song, Yue Wang, Ming Zhan, Xu Gao, Zhong Wang
Summary: This study investigates the effect of metabolic reprogramming on lineage differentiation in prostate cancer cells. The results show that metabolic reprogramming leads to antiandrogen drug resistance and tumor development, and this lineage differentiation can be reversed by the overexpression of certain genes.
MOLECULAR METABOLISM
(2022)
Article
Medicine, Research & Experimental
Mounir Bouhifd, Melvin E. Andersen, Christina Baghdikian, Kim Boekelheide, Kevin M. Crofton, Albert J. Fornace, Andre Kleensang, Henghong Li, Carolina Livi, Alexandra Maertens, Patrick D. McMullen, Michael Rosenberg, Russell Thomas, Marguerite Vantangoli, James D. Yager, Liang Zhao, Thomas Hartung
ALTEX-ALTERNATIVES TO ANIMAL EXPERIMENTATION
(2015)
Article
Pharmacology & Pharmacy
Johannes Delp, Simon Gutbier, Martin Cerff, Christin Zasada, Sebastian Niedenfuehr, Liang Zhao, Lena Smirnova, Thomas Hartung, Hanna Borlinghaus, Falk Schreiber, Joerg Bergemann, Jochem Gaetgens, Martin Beyss, Salah Azzouzi, Tanja Waldmann, Stefan Kempa, Katharina Noeh, Marcel Leist
TOXICOLOGY AND APPLIED PHARMACOLOGY
(2018)
Article
Immunology
Im-Hong Sun, Min-Hee Oh, Liang Zhao, Chirag H. Patel, Matthew L. Arwood, Wei Xu, Ada J. Tam, Richard L. Blosser, Jiayu Wen, Jonathan D. Powell
JOURNAL OF IMMUNOLOGY
(2018)
Review
Pharmacology & Pharmacy
Mounir Bouhifd, Helena T. Hogberg, Andre Kleensang, Alexandra Maertens, Liang Zhao, Thomas Hartung
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
(2014)
Article
Cell Biology
M. Signore, F. Pelacchi, S. di Martino, D. Runci, M. Biffoni, S. Giannetti, L. Morgante, M. De Majo, E. F. Petricoin, L. Stancato, L. M. Larocca, R. De Maria, R. Pallini, L. Ricci-Vitiani
CELL DEATH & DISEASE
(2014)
Article
Multidisciplinary Sciences
Aleksander Skardal, Sean V. Murphy, Mahesh Devarasetty, Ivy Mead, Hyun-Wook Kang, Young-Joon Seol, Yu Shrike Zhang, Su-Ryon Shin, Liang Zhao, Julio Aleman, Adam R. Hall, Thomas D. Shupe, Andre Kleensang, Mehmet R. Dokmeci, Sang Jin Lee, John D. Jackson, James J. Yoo, Thomas Hartung, Ali Khademhosseini, Shay Soker, Colin E. Bishop, Anthony Atala
SCIENTIFIC REPORTS
(2017)
Article
Multidisciplinary Sciences
Robert D. Leone, Liang Zhao, Judson M. Englert, Im-Meng Sun, Min-Hee Oh, Im-Hong Sun, Matthew L. Arwood, Ian A. Bettencourt, Chirag H. Patel, Jiayu Wen, Ada Tam, Richard L. Blosser, Eva Prchalova, Jesse Alt, Rana Rais, Barbara S. Slusher, Jonathan D. Powell
Article
Medicine, Research & Experimental
Min-Hee Oh, Im-Hong Sun, Liang Zhao, Robert D. Leone, Im-Meng Sun, Wei Xu, Samuel L. Collins, Ada J. Tam, Richard L. Blosser, Chirag H. Patel, Judson M. Englert, Matthew L. Arwood, Jiayu Wen, Yee Chan-Li, Lukas Tenora, Pavel Majer, Rana Rais, Barbara S. Slusher, Maureen R. Horton, Jonathan D. Powell
JOURNAL OF CLINICAL INVESTIGATION
(2020)
Article
Immunology
Samuel L. Collins, Min-Hee Oh, Im-Hong Sun, Yee Chan-Li, Liang Zhao, Jonathan D. Powell, Maureen R. Horton
Summary: Metabolic programming is closely linked to immune cell function, with mTOR signaling as a key regulator. While mTORC2 signaling is crucial for M2 macrophage generation, the role of mTORC1 signaling remains controversial. Inhibiting mTORC1 signaling enhances M1 macrophage function, despite defects in glycolytic metabolism, by inhibiting sirtuins and enhancing histone acetylation.
JOURNAL OF IMMUNOLOGY
(2021)
Article
Multidisciplinary Sciences
Fei Mo, Zhiya Yu, Peng Li, Jangsuk Oh, Rosanne Spolski, Liang Zhao, Caleb R. Glassman, Tori N. Yamamoto, Yun Chen, Filip M. Golebiowski, Dalton Hermans, Sonia Majri-Morrison, Lora K. Picton, Wei Liao, Min Ren, Xiaoxuan Zhuang, Suman Mitra, Jian-Xin Lin, Luca Gattinoni, Jonathan D. Powell, Nicholas P. Restifo, K. Christopher Garcia, Warren J. Leonard
Summary: Adoptive transfer of antigen-specific T cells is a significant advancement in cancer immunotherapy, and maintaining a stem-cell-like state before transfer is beneficial for therapeutic efficacy.
Article
Multidisciplinary Sciences
Alok Kumar Singh, Monali Praharaj, Kara A. Lombardo, Takahiro Yoshida, Andres Matoso, Alex S. Baras, Liang Zhao, Geetha Srikrishna, Joy Huang, Pankaj Prasad, Jonathan D. Powell, Max Kates, David McConkey, Drew M. Pardoll, William R. Bishai, Trinity J. Bivalacqua
Summary: This study re-engineered the BCG vaccine to express high levels of the PAMP molecule c-di-AMP, leading to augmented immune responses, enhanced induction of trained immunity, and improved antitumor efficacy in pre-clinical models of bladder cancer.
NATURE COMMUNICATIONS
(2022)
Article
Immunology
Michael D. Claiborne, Srona Sengupta, Liang Zhao, Matthew L. Arwood, Im-Meng Sun, Jiayu Wen, Elizabeth A. Thompson, Marisa Mitchell-Flack, Marikki Laiho, Jonathan D. Powell
Summary: Memory CD8(+) T cells exhibit longevity and rapid recall response. Metabolic reprogramming and mitochondrial function are important for their longevity, while the trifunctional enzyme CAD plays a critical role in promoting the rapid recall response. CAD-induced pyrimidine synthesis and ribosomal biogenesis are involved in this process.
SCIENCE IMMUNOLOGY
(2022)
Article
Multidisciplinary Sciences
Rana Rais, Kathryn M. Lemberg, Lukas Tenora, Matthew L. Arwood, Arindom Pal, Jesse Alt, Ying Wu, Jenny Lam, Joanna Marie H. Aguilar, Liang Zhao, Diane E. Peters, Carolyn Tallon, Rajeev Pandey, Ajit G. Thomas, Ranjeet P. Dash, Tanguy Seiwert, Pavel Majer, Robert D. Leone, Jonathan D. Powell, Barbara S. Slusher
Summary: 6-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist that suppresses cancer cell metabolism while enhancing the metabolic fitness of tumor CD8+ T cells. The development of DON was halted due to dose-limiting gastrointestinal toxicities. In order to overcome this, a DON peptide prodrug, DRP-104, was designed and showed improved tolerability and enhanced efficacy in tumor regression. The effect of DRP-104 is dependent on CD8+ T cells and results in strong immunologic memory.
Article
Chemistry, Analytical
Leslie Myint, Andre Kleensang, Liang Zhao, Thomas Hartung, Kasper D. Hansen
ANALYTICAL CHEMISTRY
(2017)