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

Burgener, Anne-Valérie and Bantug, Glenn R. and Meyer, Benedikt J. and Higgins, Rebecca and Ghosh, Adhideb and Bignucolo, Olivier and Ma, Eric H. and Loeliger, Jordan and Unterstab, Gunhild and Geigges, Marco and Steiner, Rebekah and Enamorado, Michel and Ivanek, Robert and Hunziker, Danielle and Schmidt, Alexander and Müller-Durovic, Bojana and Grählert, Jasmin and Epple, Raja and Dimeloe, Sarah and Lötscher, Jonas and Sauder, Ursula and Ebnöther, Monika and Burger, Bettina and Heijnen, Ingmar and Martínez-Cano, Sarai and Cantoni, Nathan and Brücker, Rolf and Kahlert, Christian R. and Sancho, David and Jones, Russell G. and Navarini, Alexander and Recher, Mike and Hess, Christoph. (2019) SDHA gain-of-function engages inflammatory mitochondrial retrograde signaling via KEAP1-Nrf2. Nature Immunology, 20 (10). pp. 1311-1321.

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Official URL: https://edoc.unibas.ch/72203/

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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.
Faculties and Departments:03 Faculty of Medicine > Bereich Spezialfächer (Klinik) > Dermatologie USB > Dermatologie (Navarini)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Spezialfächer (Klinik) > Dermatologie USB > Dermatologie (Navarini)
UniBasel Contributors:Navarini, Alexander and Burger, Bettina
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Nature Publishing Group
ISSN:1529-2916
e-ISSN:1529-2916
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:30 Sep 2020 12:23
Deposited On:10 Jul 2020 09:29

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