Publication
SDHA gain-of-function engages inflammatory mitochondrial retrograde signaling via KEAP1-Nrf2
Journal Paper/Review - Sep 16, 2019
Burgener Anne-Valérie, Dimeloe Sarah, Lötscher Jonas, Sauder Ursula, Ebnöther Monika, Burger Bettina, Heijnen Ingmar, Martínez-Cano Sarai, Cantoni Nathan, Brücker Rolf, Kahlert Christian, Sancho David, Jones Russell G, Navarini Alexander, Recher Mike, Epple Raja, Grählert Jasmin, Müller-Durovic Bojana, Bantug Glenn R, Meyer Benedikt J, Higgins Rebecca, Ghosh Adhideb, Bignucolo Olivier, Ma Eric H, Loeliger Jordan, Unterstab Gunhild, Geigges Marco, Steiner Rebekah, Enamorado Michel, Ivanek Robert, Hunziker Danielle, Schmidt Alexander, Hess Christoph
Units
PubMed
Doi
Citation
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Journal
Publication Date
Issn Electronic
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Brief description/objective
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.