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

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

MED - Medical Sciences

Research output: Contribution to journal › Article › peer-review

105 Citations (Scopus)

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.

Original language	English
Article number	6750
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7750
Publication status	Published - 2015 Apr 10

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/ncomms7750

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@article{4ce0e3c88cda44b78767459631986589,

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 mitochondriahigh 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.",

author = "Jang, {Kyoung Jin} and Hiroto Mano and Koji Aoki and Tatsunari Hayashi and Akihiko Muto and Yukiko Nambu and Katsu Takahashi and Katsuhiko Itoh and Shigeru Taketani and Nutt, {Stephen L.} and Kazuhiko Igarashi and Akira Shimizu and Manabu Sugai",

note = "Funding Information: We thank Drs F. Alt (Harvard University), U. Basu (Harvard University) and J. Chaudhuri (Memorial Sloan–Kettering Cancer Center) for providing AID antibody; Drs K. Iwai (Kyoto University), Y. Sasaki (Kyoto University), H. Arakawa (National Cancer Center) and Y. Yokota (Fukui University) for discussion of the findings; Drs K. Ochiai (Tohoku University) and Y. Yokota (Fukui University) for critical reading of the manuscript; Dr M. Minami (Kyoto University) for comments on mitochondrial assay; Ms K. Furuta and Mr H. Koda (Kyoto University) for technical assistance in electron microscopy; Drs Okuno (Kyoto University) and Fukuura (PRIMETECH Corp) for the XF96 assay; Dr Takatani (Kyoto University) for comments on this study; and Mr K. Yoshida (Kyoto University) for supporting experiments. We thank Enago (www.ena-go.jp) for English language review. This work was supported in part by grants-in-aid for Science Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan. S.L.N. was supported by an Australian Research Council Future Fellowship and Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIIS. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited. All rights reserved.",

year = "2015",

month = apr,

day = "10",

doi = "10.1038/ncomms7750",

language = "English",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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T1 - Mitochondrial function provides instructive signals for activation-induced B-cell fates

AU - Jang, Kyoung Jin

AU - Mano, Hiroto

AU - Aoki, Koji

AU - Hayashi, Tatsunari

AU - Muto, Akihiko

AU - Nambu, Yukiko

AU - Takahashi, Katsu

AU - Itoh, Katsuhiko

AU - Taketani, Shigeru

AU - Nutt, Stephen L.

AU - Igarashi, Kazuhiko

AU - Shimizu, Akira

AU - Sugai, Manabu

N1 - Funding Information: We thank Drs F. Alt (Harvard University), U. Basu (Harvard University) and J. Chaudhuri (Memorial Sloan–Kettering Cancer Center) for providing AID antibody; Drs K. Iwai (Kyoto University), Y. Sasaki (Kyoto University), H. Arakawa (National Cancer Center) and Y. Yokota (Fukui University) for discussion of the findings; Drs K. Ochiai (Tohoku University) and Y. Yokota (Fukui University) for critical reading of the manuscript; Dr M. Minami (Kyoto University) for comments on mitochondrial assay; Ms K. Furuta and Mr H. Koda (Kyoto University) for technical assistance in electron microscopy; Drs Okuno (Kyoto University) and Fukuura (PRIMETECH Corp) for the XF96 assay; Dr Takatani (Kyoto University) for comments on this study; and Mr K. Yoshida (Kyoto University) for supporting experiments. We thank Enago (www.ena-go.jp) for English language review. This work was supported in part by grants-in-aid for Science Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan. S.L.N. was supported by an Australian Research Council Future Fellowship and Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIIS. Publisher Copyright: © 2015 Macmillan Publishers Limited. All rights reserved.

PY - 2015/4/10

Y1 - 2015/4/10

N2 - 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 mitochondriahigh 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.

AB - 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 mitochondriahigh 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.

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U2 - 10.1038/ncomms7750

DO - 10.1038/ncomms7750

M3 - Article

C2 - 25857523

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SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 6750

ER -

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

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