Mitochondrial function provides instructive signals for activation-induced B-cell fates

Kyoung-Jin Jang; Hiroto Mano; Koji Aoki; Tatsunari Hayashi; Akihiko Muto; Yukiko Nambu; Katsu Takahashi; Katsuhiko Itoh; Shigeru Taketani; Stephen L Nutt; Kazuhiko Igarashi; Akira Shimizu; Manabu Sugai

doi:10.1038/ncomms7750

Mitochondrial function provides instructive signals for activation-induced B-cell fates

Nat Commun. 2015 Apr 10:6:6750. doi: 10.1038/ncomms7750.

Authors

Affiliations

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 Pharmacology, School of Medicine, University of Fukui, 23-3 Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan.
³ 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.
⁴ Department of Oral and Maxillofacial Surgery, Kyoto University Hospital, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
⁵ Department of Clinical Molecular Biology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
⁶ Department of Biotechnology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan.
⁷ 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.
⁸ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
B-Lymphocyte Subsets / cytology
B-Lymphocyte Subsets / immunology
B-Lymphocyte Subsets / metabolism*
Basic-Leucine Zipper Transcription Factors / deficiency
Basic-Leucine Zipper Transcription Factors / genetics
Cell Differentiation
Cell Tracking
Gene Expression
Heme / biosynthesis
Immunoglobulin Class Switching / genetics
Lymphocyte Activation
Male
Membrane Potential, Mitochondrial / immunology
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria / metabolism*
Plasma Cells / cytology
Plasma Cells / immunology
Plasma Cells / metabolism*
Positive Regulatory Domain I-Binding Factor 1
Primary Cell Culture
Protoporphyrins / metabolism
Reactive Oxygen Species / immunology
Reactive Oxygen Species / metabolism*
Signal Transduction*
Stochastic Processes
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

Bach2 protein, mouse
Basic-Leucine Zipper Transcription Factors
Prdm1 protein, mouse
Protoporphyrins
Reactive Oxygen Species
Transcription Factors
Heme
protoporphyrin IX
Positive Regulatory Domain I-Binding Factor 1