SDHA gain-of-function engages inflammatory mitochondrial retrograde signaling via KEAP1-Nrf2

Research output: Contribution to journalArticle

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SDHA gain-of-function engages inflammatory mitochondrial retrograde signaling via KEAP1-Nrf2. / Burgener, Anne-Valerie; Bantug, Glenn; Meyer, B; Higgins, R; Ghosh, A; Bignucolo, O; Ma, Eric; Loeliger, J; Unterstab, Gunhild; Geigges, M; Steiner, Rebekah; Enamorado, M; Ivanek, R; Hunziker, D; Schmidt, R; Muller_Durovic, B; Graehlert, Jasmin; Epple, R; Dimeloe, Sarah; Lotscher, J; Sauder, U; Ebnother, M; Burger, B; Heijnen, I; Martinez-Cano, S; Cantoni, N; Brucker, R; Kahlert, CR; Sancho, D; Jones, Russell G.; Navarini, A; Recher, Mike; Hess, Christoph.

In: Nature Immunology, Vol. 20, No. 10, 01.10.2019, p. 1311–1321.

Research output: Contribution to journalArticle

Harvard

Burgener, A-V, Bantug, G, Meyer, B, Higgins, R, Ghosh, A, Bignucolo, O, Ma, E, Loeliger, J, Unterstab, G, Geigges, M, Steiner, R, Enamorado, M, Ivanek, R, Hunziker, D, Schmidt, R, Muller_Durovic, B, Graehlert, J, Epple, R, Dimeloe, S, Lotscher, J, Sauder, U, Ebnother, M, Burger, B, Heijnen, I, Martinez-Cano, S, Cantoni, N, Brucker, R, Kahlert, CR, Sancho, D, Jones, RG, Navarini, A, Recher, M & Hess, C 2019, 'SDHA gain-of-function engages inflammatory mitochondrial retrograde signaling via KEAP1-Nrf2', Nature Immunology, vol. 20, no. 10, pp. 1311–1321. https://doi.org/10.1038/s41590-019-0482-2

APA

Burgener, A-V., Bantug, G., Meyer, B., Higgins, R., Ghosh, A., Bignucolo, O., Ma, E., Loeliger, J., Unterstab, G., Geigges, M., Steiner, R., Enamorado, M., Ivanek, R., Hunziker, D., Schmidt, R., Muller_Durovic, B., Graehlert, J., Epple, R., Dimeloe, S., ... Hess, C. (2019). SDHA gain-of-function engages inflammatory mitochondrial retrograde signaling via KEAP1-Nrf2. Nature Immunology, 20(10), 1311–1321. https://doi.org/10.1038/s41590-019-0482-2

Vancouver

Burgener A-V, Bantug G, Meyer B, Higgins R, Ghosh A, Bignucolo O et al. SDHA gain-of-function engages inflammatory mitochondrial retrograde signaling via KEAP1-Nrf2. Nature Immunology. 2019 Oct 1;20(10):1311–1321. https://doi.org/10.1038/s41590-019-0482-2

Author

Burgener, Anne-Valerie ; Bantug, Glenn ; Meyer, B ; Higgins, R ; Ghosh, A ; Bignucolo, O ; Ma, Eric ; Loeliger, J ; Unterstab, Gunhild ; Geigges, M ; Steiner, Rebekah ; Enamorado, M ; Ivanek, R ; Hunziker, D ; Schmidt, R ; Muller_Durovic, B ; Graehlert, Jasmin ; Epple, R ; Dimeloe, Sarah ; Lotscher, J ; Sauder, U ; Ebnother, M ; Burger, B ; Heijnen, I ; Martinez-Cano, S ; Cantoni, N ; Brucker, R ; Kahlert, CR ; Sancho, D ; Jones, Russell G. ; Navarini, A ; Recher, Mike ; Hess, Christoph. / SDHA gain-of-function engages inflammatory mitochondrial retrograde signaling via KEAP1-Nrf2. In: Nature Immunology. 2019 ; Vol. 20, No. 10. pp. 1311–1321.

Bibtex

@article{629d84259baf4a1d98fd4e439211bdc4,
title = "SDHA gain-of-function engages inflammatory mitochondrial retrograde signaling via KEAP1-Nrf2",
abstract = "Whether screening the metabolic activity of immune cells facilitates discovery of molecular pathology remains unknown. Here we prospectively screened the extracellular acidification rate as a measure of glycolysis and the oxygen consumption rate as a measure of mitochondrial respiration in B cells from patients with primary antibody deficiency. The highest oxygen consumption rate values were detected in three study participants with persistent polyclonal B cell lymphocytosis (PPBL). Exome sequencing identified germline mutations in SDHA, which encodes succinate dehydrogenase subunit A, in all three patients with PPBL. SDHA gain-of-function led to an accumulation of fumarate in PPBL B cells, which engaged the KEAP1–Nrf2 system to drive the transcription of genes encoding inflammatory cytokines. In a single patient trial, blocking the activity of the cytokine interleukin-6 in vivo prevented systemic inflammation and ameliorated clinical disease. Overall, our study has identified pathological mitochondrial retrograde signaling as a disease modifier in primary antibody deficiency.",
author = "Anne-Valerie Burgener and Glenn Bantug and B Meyer and R Higgins and A Ghosh and O Bignucolo and Eric Ma and J Loeliger and Gunhild Unterstab and M Geigges and Rebekah Steiner and M Enamorado and R Ivanek and D Hunziker and R Schmidt and B Muller_Durovic and Jasmin Graehlert and R Epple and Sarah Dimeloe and J Lotscher and U Sauder and M Ebnother and B Burger and I Heijnen and S Martinez-Cano and N Cantoni and R Brucker and CR Kahlert and D Sancho and Jones, {Russell G.} and A Navarini and Mike Recher and Christoph Hess",
year = "2019",
month = oct
day = "1",
doi = "10.1038/s41590-019-0482-2",
language = "English",
volume = "20",
pages = "1311–1321",
journal = "Nature Immunology",
issn = "1529-2908",
publisher = "Nature Publishing Group",
number = "10",

}

RIS

TY - JOUR

T1 - SDHA gain-of-function engages inflammatory mitochondrial retrograde signaling via KEAP1-Nrf2

AU - Burgener, Anne-Valerie

AU - Bantug, Glenn

AU - Meyer, B

AU - Higgins, R

AU - Ghosh, A

AU - Bignucolo, O

AU - Ma, Eric

AU - Loeliger, J

AU - Unterstab, Gunhild

AU - Geigges, M

AU - Steiner, Rebekah

AU - Enamorado, M

AU - Ivanek, R

AU - Hunziker, D

AU - Schmidt, R

AU - Muller_Durovic, B

AU - Graehlert, Jasmin

AU - Epple, R

AU - Dimeloe, Sarah

AU - Lotscher, J

AU - Sauder, U

AU - Ebnother, M

AU - Burger, B

AU - Heijnen, I

AU - Martinez-Cano, S

AU - Cantoni, N

AU - Brucker, R

AU - Kahlert, CR

AU - Sancho, D

AU - Jones, Russell G.

AU - Navarini, A

AU - Recher, Mike

AU - Hess, Christoph

PY - 2019/10/1

Y1 - 2019/10/1

N2 - Whether screening the metabolic activity of immune cells facilitates discovery of molecular pathology remains unknown. Here we prospectively screened the extracellular acidification rate as a measure of glycolysis and the oxygen consumption rate as a measure of mitochondrial respiration in B cells from patients with primary antibody deficiency. The highest oxygen consumption rate values were detected in three study participants with persistent polyclonal B cell lymphocytosis (PPBL). Exome sequencing identified germline mutations in SDHA, which encodes succinate dehydrogenase subunit A, in all three patients with PPBL. SDHA gain-of-function led to an accumulation of fumarate in PPBL B cells, which engaged the KEAP1–Nrf2 system to drive the transcription of genes encoding inflammatory cytokines. In a single patient trial, blocking the activity of the cytokine interleukin-6 in vivo prevented systemic inflammation and ameliorated clinical disease. Overall, our study has identified pathological mitochondrial retrograde signaling as a disease modifier in primary antibody deficiency.

AB - Whether screening the metabolic activity of immune cells facilitates discovery of molecular pathology remains unknown. Here we prospectively screened the extracellular acidification rate as a measure of glycolysis and the oxygen consumption rate as a measure of mitochondrial respiration in B cells from patients with primary antibody deficiency. The highest oxygen consumption rate values were detected in three study participants with persistent polyclonal B cell lymphocytosis (PPBL). Exome sequencing identified germline mutations in SDHA, which encodes succinate dehydrogenase subunit A, in all three patients with PPBL. SDHA gain-of-function led to an accumulation of fumarate in PPBL B cells, which engaged the KEAP1–Nrf2 system to drive the transcription of genes encoding inflammatory cytokines. In a single patient trial, blocking the activity of the cytokine interleukin-6 in vivo prevented systemic inflammation and ameliorated clinical disease. Overall, our study has identified pathological mitochondrial retrograde signaling as a disease modifier in primary antibody deficiency.

U2 - 10.1038/s41590-019-0482-2

DO - 10.1038/s41590-019-0482-2

M3 - Article

VL - 20

SP - 1311

EP - 1321

JO - Nature Immunology

JF - Nature Immunology

SN - 1529-2908

IS - 10

ER -