SDHA gain-of-function engages inflammatory mitochondrial retrograde signaling via KEAP1-Nrf2
| Autor: | Jonas Lötscher, Christoph Hess, Bojana Müller-Durovic, Rebekah Steiner, Olivier Bignucolo, Rebecca Higgins, David Sancho, Mike Recher, Bettina Burger, Gunhild Unterstab, Michel Enamorado, Alexander A. Navarini, Anne-Valérie Burgener, Ursula Sauder, Jasmin Grählert, Rolf Brücker, Glenn R. Bantug, Sarai Martínez-Cano, Eric H. Ma, Marco Geigges, Alexander Schmidt, Jordan Loeliger, Ingmar Heijnen, Robert Ivanek, Benedikt J. Meyer, Russell G. Jones, Sarah Dimeloe, Nathan Cantoni, Danielle Hunziker, Christian R Kahlert, Monika Ebnöther, Raja Epple, Adhideb Ghosh |
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| Přispěvatelé: | Gebert Rüf Foundation, Swiss National Science Foundation, Swiss National Supercomputing Center, Burgener, Anne-Valérie [0000-0002-8119-8703], Ghosh, Adhideb [0000-0002-5160-4571], Bignucolo, Olivier [0000-0003-4735-049X], Steiner, Rebekah [0000-0001-8921-3202], Ivanek, Robert [0000-0002-8403-056X], Schmidt, Alexander [0000-0002-3149-2381], Burger, Bettina [0000-0002-7686-0176], Cantoni, Nathan [0000-0001-9002-9015], Kahlert, Christian R [0000-0002-0784-3276], Sancho, David [0000-0003-2890-3984], Hess, Christoph [0000-0003-0364-8825], Apollo - University of Cambridge Repository |
| Rok vydání: | 2019 |
| Předmět: |
NF-E2-Related Factor 2
medicine.medical_treatment Immunology Cell Respiration SDHA Anti-Inflammatory Agents Lymphocytosis Biology Systemic inflammation Whole Exome Sequencing Proinflammatory cytokine 03 medical and health sciences 0302 clinical medicine Immune system Germline mutation Oxygen Consumption Fumarates Exome Sequencing medicine Immunology and Allergy Humans Prospective Studies Cells Cultured 030304 developmental biology Inflammation 0303 health sciences B-Lymphocytes Kelch-Like ECH-Associated Protein 1 Interleukin-6 Electron Transport Complex II 3. Good health Mitochondria Cytokine 030220 oncology & carcinogenesis Mutation Retrograde signaling Cancer research Signal transduction medicine.symptom Glycolysis Signal Transduction |
| Zdroj: | Nature immunology. 20(10) |
| ISSN: | 1529-2916 |
| Popis: | 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. We thank the patients that participated in the study, the flow sorting team and the microscopy core facility of the Department of Biomedicine, University and University Hospital of Basel, the Blood Donor Center affiliated with the University Hospital of Basel, as well as G. Hoenger, U. Duthaler, C. Gasser, J. Hirsiger, C. Berger, T. Daikeler, F. Marquardsen and F. Baldin for technical support and/or help with the clinical management of patients. Funding was provided by Gebert Rüf Foundation (grant no. GRS-058/14 to C.H. and M.R.); Swiss National Science Foundation (SNSF) (grant nos. 31003A_172848 to C.H. and PP00P3_181038 to M.R.). This work was further supported by a grant from the Swiss National Supercomputing Center (project ID SM09). Sí |
| Databáze: | OpenAIRE |
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