K+K+K+O2■The overarching goal of our laboratory is to understand the role of cel-Lysosomepro-IL-1βIL-1ββIL-1βK+■Lyso■ATP■pH■NLRP3(PYCARD(CASP1pro(IL(1βIL(1ββIL(1β52ROSROSNLRP3-PYCARD-CASP1ROSROSNLRP3-PYCARD-CASP1Activator screenSuppressor screens+ 11280 chemicalsCombinatorial chemical screen+ Model buildingpHATPEx vivo / in vivo analysisModel refinement1232?X??123?XLysosomepro-IL-1βIL-1ββIL-1βFigure: Schematic of our chemical screening strategy to understand the role of mitochondria in NLRP3 inflammasome activationlular metabolism in the pathogenesis of complex diseases. Research over the past decades has shown that monogenic mutations in metabolic pathways cause a wide variety of human diseases. However, more recent studies have highlighted the role of cellular metabolism in the development of complex human diseases. Our laboratory in particular has been studying the function of mitochondrial energy metabolism, which is associated with neurodegeneration, cardiovascular disease, type 2 diabetes, and aging. We hope to identify novel pathways that restore or improve mitochondrial function through genetic and chemical screens and to examine their potential therapeutic value using geneti-cally engineered mouse models and unique chemical probes.Mitochondria in inflammationWe recently used our screening toolbox to identify chemicals that can acti-vate and suppress an inflammatory pathway called the NLRP3 inflammasome. We discovered niclosamide (mitochondrial uncoupler) as a new activator of this pathway. By pursuing the mechanism of action of niclosamide, we learned how mitochondrial energy metabolism, in partnership with glycolysis, is linked to inflammasome activation.We are also extending our screening approach to understand how other en-vironmental toxins and particles activate the inflammasome. We are continuing to explore how different key cellular processes, especially in regards to cellular metabolism, work together during inflammasome activation.Mitochondria in neuronal deathWe have begun to study how mitochondrial stress leads to neuronal cell death in the context of Parkinson’s disease. In collaboration with our colleagues from the Luxembourg Centre for Systems Biomedicine (LCSB), we are using focused chemical screens and metabolomics to understand how metabolic pathways respond to mitochondrial stress. We hope to understand how mito-chondrial perturbation triggers various stress response pathways and to search for ways to delay or avert neuronal cell death.Recent Major PublicationsTakeuchi T, Miyauchi E, Kanaya T, Kato T, Nakanishi Y, Watanabe T, Kitami T, Taida T, Sasaki T, Negishi H, Shima-moto S, Matsuyama A, Kimura I, Williams IR, Ohara O, Ohno H. Acetate differentially regulates IgA reactivity to commensal bacteria. Nature 595, 560-564 (2021)Kitami T, Fukuda S, Kato T, Yamaguti K, Nakatomi Y, Yamano E, Kataoka Y, Mizuno K, Tsuboi Y, Kogo Y, Suzuki H, Itoh M, Morioka MS, Kawaji H, Koseki H, Kikuchi J, Hayashizaki Y, Ohno H, Kuratsune H, Watanabe Y. Deep phenotyping of myalgic encephalomyelitis/chronic fatigue syndrome in Japanese population. Sci Rep 10, 19933 (2020)Tran UT, Kitami T. Niclosamide activates the NLRP3 inflammasome by intracellular acidification and mito-chondrial inhibition. Commun Biol 2, 2 (2019)Laboratory for Metabolic NetworksTeam Leader: Toshimori Kitami
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