title: Mitochondrial function provides instructive signals for activation-induced B-cell fates.
abstract: During immune reactions, functionally distinct B-cell subsets are generated by stochastic processes, including class-switch recombination (CSR) and plasma cell differentiation (PCD). In this study, we show a strong association between individual B-cell fates and mitochondrial functions. CSR occurs specifically in activated B cells with increased mitochondrial mass and membrane potential, which augment mitochondrial reactive oxygen species (mROS), whereas PCD occurs in cells with decreased mitochondrial mass and potential. These events are consequences of initial slight changes in mROS in mitochondria(high) B-cell populations. In CSR-committed cells, mROS attenuates haeme synthesis by inhibiting ferrous ion addition to protoporphyrin IX, thereby maintaining Bach2 function. Reduced mROS then promotes PCD by increasing haeme synthesis. In PCD-committed cells, Blimp1 reduces mitochondrial mass, thereby reducing mROS levels. Identifying mROS as a haeme synthesis regulator increases the understanding of mechanisms regulating haeme homeostasis and cell fate determination after B-cell activation.
authors: Department of Experimental Therapeutics, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors: Kyoung-Jin
authors: KJ
authors: Jang
authors: Department of Experimental Therapeutics, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors: Hiroto
authors: H
authors: Mano
authors: Division of Pharmacology, School of Medicine, University of Fukui, 23-3 Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan.
authors: Koji
authors: K
authors: Aoki
authors: Department of Experimental Therapeutics, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors: Tatsunari
authors: T
authors: Hayashi
authors: 1] Department of Biochemistry, Tohoku University Graduate School of Medicine, Seiryo-machi 2-1, Aoba-ku, Sendai, Miyagi 980-8575, Japan [2] CREST, Japan Science and Technology Agency, Seiryo-machi 2-1, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
authors: Akihiko
authors: A
authors: Muto
authors: Department of Experimental Therapeutics, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors: Yukiko
authors: Y
authors: Nambu
authors: Department of Oral and Maxillofacial Surgery, Kyoto University Hospital, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors: Katsu
authors: K
authors: Takahashi
authors: Department of Clinical Molecular Biology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors: Katsuhiko
authors: K
authors: Itoh
authors: Department of Biotechnology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan.
authors: Shigeru
authors: S
authors: Taketani
authors: 1] The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
authors: Stephen L
authors: SL
authors: Nutt
authors: 1] Department of Biochemistry, Tohoku University Graduate School of Medicine, Seiryo-machi 2-1, Aoba-ku, Sendai, Miyagi 980-8575, Japan [2] CREST, Japan Science and Technology Agency, Seiryo-machi 2-1, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
authors: Kazuhiko
authors: K
authors: Igarashi
authors: Department of Experimental Therapeutics, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors: Akira
authors: A
authors: Shimizu
authors: 1] Department of Experimental Therapeutics, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan [2] Division of Molecular Genetics, Department of Biochemistry and Bioinformative Sciences, School of Medicine, University of Fukui, 23-3 Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan.
authors: Manabu
authors: M
authors: Sugai
mesh_terms: D000818:Animals; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D050976:Basic-Leucine Zipper Transcription Factors / Q000172:deficiency / Q000235:genetics; D002454:Cell Differentiation; D058948:Cell Tracking; D015870:Gene Expression; D006418:Heme / Q000096:biosynthesis; D017578:Immunoglobulin Class Switching / Q000235:genetics; D008213:Lymphocyte Activation; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D061251:Primary Cell Culture; D011524:Protoporphyrins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D013269:Stochastic Processes; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C102109:Bach2 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; C513258:Prdm1 protein, mouse; D011524:Protoporphyrins; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D006418:Heme; C028025:protoporphyrin IX; D000074462:Positive Regulatory Domain I-Binding Factor 1