XX1XXXXX2X34?...Mitochondria are dynamic organelles central to energy homeostasis, inter-48Chemical screensCellular modelsMolecular insights...Stress typeIn vivo analysisMitochondrial tool compoundsCell typeTowards our goal, we initiated chemical screens focusing on the role of mi-tochondria in inflammation and neuronal cell death, both of which converge to accelerate neurodegenerative processes. In macrophages, we identified small molecules that specifically block mitochondrial damage-induced activation of the NLRP3 inflammasome pathway. In neuronal cells, we identified small mol-ecules that block neuronal death triggered by mitochondrial inhibition. We are currently working to test our tool compounds and molecular targets in mouse models of Parkinson’s disease and mitochondrial disease. We are also working with collaborators to identify chemicals that improve the bioenergetic output of mitochondria in muscle. Through these efforts, we hope to generate a list of mitochondrial tool compounds that can be used to gain molecular insights and new therapeutic targets for diseases of mitochondrial dysfunction.In addition, we are examining the role of mitochondria in other complex disease pathways by taking advantage of large-scale omics datasets generated at RIKEN IMS. We hope that our multi-omics and chemical biology efforts will not only help clarify the role of mitochondria in complex diseases but will also point to common therapeutic strategies for a variety of mitochondria-related disorders.mediary metabolism, ion homeostasis, and cell death. Inherited defects in mitochondria cause the most common inborn errors of metabolism, but a growing body of evidence also links mitochondria to more complex diseases in-cluding type 2 diabetes, cardiovascular disease, and neurodegeneration. Despite our basic understanding of mitochondrial functions, the precise mechanisms by which mitochondria participate in disease pathogenesis remain largely unan-swered. The long-term goal of our laboratory is to use our expertise in chemical biology and genomics to critically evaluate the role of mitochondria in disease pathways and to develop novel therapeutics centered on mitochondria. Figure: Schematic of our chemical screening strategy for uncovering the role of mitochon-dria in complex disease pathways(1) Cell-based chemical screens are performed across cell types involved in mitochondria-related diseases. (2) The resulting datasets are analyzed to identify tool compounds that protect cells from mitochondrial dys-function across different “stress types” and “cell types”. (3) The datasets are used to generate novel hypotheses regarding molecular mechanisms of mitochondria-related diseases and to (4) test new therapeutic targets in mouse models of human diseases.Recent Major PublicationsKobayashi A, Azuma K, Takeiwa T, Kitami T, Horie K, Ikeda K, Inoue S. FRET-based respirasome assembly screen defines potential therapeutic intervention that improves muscle mitochondrial respiration and exercise performance. Nat Commun 14, 312 (2023)Takeuchi T, Kubota T, Nakanishi Y, Tsugawa H, Suda W, Kwon AT, Yazaki J, Ikeda K, Nemoto S, Mochizuki Y, Kitami T, Yugi K, Mizuno Y, Yamamichi N, Yamazaki T, Takamoto I, Kubota N, Kadowaki T, Arner E, Carninci P, Ohara O, Arita M, Hattori M, Koyasu S, Ohno H. Gut mi-crobiota carbohydrate metabolism contributes to insulin resistance. Nature 621, 389-395 (2023)Invited presentationsKitami T. “Dissecting the mitochondrial stress response network using chemical screening and metabolomics” Symposium. Japanese Biochemical Society Annual Meeting (Fukuoka, Japan) November 2023Laboratory for Metabolic NetworksTeam Leader: Toshimori Kitami
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