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
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
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
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
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)
Review
Biochemistry & Molecular Biology
Maurizio Cortada, Soledad Levano, Daniel Bodmer
Summary: Hearing loss affects many people worldwide, especially with the increasing elderly population, leading to a growing number of individuals suffering from hearing loss. Current treatment options are limited to hearing aids or cochlea implants, but the development of regenerative therapies or cell survival pathways may offer new directions for future treatments.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Endocrinology & Metabolism
Huafang Jiang, Ahmad Alahmad, Song Fu, Xiaoling Fu, Zhimei Liu, Xiaodi Han, Lanlan Li, Tianyu Song, Manting Xu, Shanshan Liu, Junling Wang, Buthaina Albash, Ahmad Alaqeel, Vasilescu Catalina, Holger Prokisch, Robert W. Taylor, Robert McFarland, Fang Fang
Summary: This study reports three novel pathogenic MPC1 variants in six patients from three unrelated families, expanding the clinical phenotypes and genotypes associated with MPC deficiency. The study also suggests glutamine as a potential therapy for MPC deficiency.
JOURNAL OF INHERITED METABOLIC DISEASE
(2022)
Article
Dermatology
Aimee Flores, Sekyu Choi, Ya-Chieh Hsu, William E. Lowry
Summary: Inhibition of pyruvate entry into mitochondria has been found to accelerate the hair cycle, even in cases of refractory hair loss, leading to the formation of histologically normal hair follicles within a short period of time. This suggests a versatile treatment strategy for alopecia in humans.
EXPERIMENTAL DERMATOLOGY
(2021)
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
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.
Article
Dermatology
Andrew White, Aimee Flores, Jessica Ong, William E. Lowry
EXPERIMENTAL DERMATOLOGY
(2016)
Article
Dermatology
Aimee Flores, William Grant, Andrew C. White, Phillip Scumpia, Rie Takahashi, William E. Lowry
EXPERIMENTAL DERMATOLOGY
(2016)
Review
Dermatology
William E. Lowry, Aimee Flores, Andrew C. White
JOURNAL OF INVESTIGATIVE DERMATOLOGY
(2016)
Article
Cell Biology
Candice Sun Hong, Nicholas A. Graham, Wen Gu, Carolina Espindola Camacho, Vei Mah, Erin L. Maresh, Mohammed Alavi, Lora Bagryanova, Pascal A. L. Krotee, Brian K. Gardner, Iman Saramipoor Behbahan, Steve Horvath, David Chia, Ingo K. Mellinghoff, Sara A. Hurvitz, Steven M. Dubinett, Susan E. Critchlow, Siavash K. Kurdistani, Lee Goodglick, Daniel Braas, Thomas G. Graeber, Heather R. Christofk
Article
Cell Biology
Aimee Flores, John Schell, Abigail S. Krall, David Jelinek, Matilde Miranda, Melina Grigorian, Daniel Braas, Andrew C. White, Jessica L. Zhou, Nicholas A. Graham, Thomas Graeber, Pankaj Seth, Denis Evseenko, Hilary A. Coller, Jared Rutter, Heather R. Christofk, William E. Lowry
NATURE CELL BIOLOGY
(2017)
Article
Cell Biology
John C. Schell, Dona R. Wisidagama, Claire Bensard, Helong Zhao, Peng Wei, Jason Tanner, Aimee Flores, Jeffrey Mohlman, Lise K. Sorensen, Christian S. Earl, Kristofor A. Olson, Ren Miao, T. Cameron Waller, Don Delker, Priyanka Kanth, Lei Jiang, Ralph J. DeBerardinis, Mary P. Bronner, Dean Y. Li, James E. Cox, Heather R. Christofk, William E. Lowry, Carl S. Thummel, Jared Rutter
NATURE CELL BIOLOGY
(2017)
Article
Cell Biology
Fang Huang, Min Ni, Milind D. Chalishazar, Kenneth E. Huffman, Jiyeon Kim, Ling Cai, Xiaolei Shi, Feng Cai, Lauren G. Zacharias, Abbie S. Ireland, Kailong Li, Wen Gu, Akash K. Kaushik, Xin Liu, Adi F. Gazdar, Trudy G. Oliver, John D. Minna, Zeping Hu, Ralph J. DeBerardinis
Article
Multidisciplinary Sciences
David Jelinek, Aimee Flores, Melanie Uebelhoer, Vincent Pasque, Kathrin Plath, M. Luisa Iruela-Arispe, Heather R. Christofk, William E. Lowry, Hilary A. Coller
JOVE-JOURNAL OF VISUALIZED EXPERIMENTS
(2018)
Article
Biochemistry & Molecular Biology
William J. Sullivan, Peter J. Mullen, Ernst W. Schmid, Aimee Flores, Milica Momcilovic, Mark S. Sharpley, David Jelinek, Andrew E. Whiteley, Matthew B. Maxwell, Blake R. Wilde, Utpal Banerjee, Hilary A. Coller, David B. Shackelford, Daniel Braas, Donald E. Ayer, Thomas Q. de Aguiar Vallim, William E. Lowry, Heather R. Christofk
Article
Multidisciplinary Sciences
A. Flores, S. Sandoyal-Gonzalez, R. Takahashi, A. Krall, L. Sathe, L. Wei, C. Radu, J. Jolly, N. Graham, H. R. Christofk, W. E. Lowry
NATURE COMMUNICATIONS
(2019)
Article
Multidisciplinary Sciences
Alpaslan Tasdogan, Brandon Faubert, Vijayashree Ramesh, Jessalyn M. Ubellacker, Bo Shen, Ashley Solmonson, Malea M. Murphy, Zhimin Gu, Wen Gu, Misty Martin, Stacy Y. Kasitinon, Travis Vandergriff, Thomas P. Mathews, Zhiyu Zhao, Dirk Schadendorf, Ralph J. DeBerardinis, Sean J. Morrison
Article
Endocrinology & Metabolism
Jiyeon Kim, Hyun Min Lee, Feng Cai, Bookyung Ko, Chendong Yang, Elizabeth L. Lieu, Nefertiti Muhammad, Shawn Rhyne, Kailong Li, Mohamed Haloul, Wen Gu, Brandon Faubert, Akash K. Kaushik, Ling Cai, Sahba Kasiri, Ummay Marriam, Kien Nham, Luc Girard, Hui Wang, Xiankai Sun, James Kim, John D. Minna, Keziban Unsal-Kacmaz, Ralph J. DeBerardinis