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

Anne-Valerie Burgener, Glenn Bantug, B Meyer, R Higgins, A Ghosh, O Bignucolo, Eric Ma, J Loeliger, Gunhild Unterstab, M Geigges, Rebekah Steiner, M Enamorado, R Ivanek, D Hunziker, R Schmidt, B Muller_Durovic, Jasmin Graehlert, R Epple, Sarah Dimeloe, J LotscherU Sauder, M Ebnother, B Burger, I Heijnen, S Martinez-Cano, N Cantoni, R Brucker, CR Kahlert, D Sancho, Russell G. Jones, A Navarini, Mike Recher, Christoph Hess

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1311–1321
Number of pages11
JournalNature Immunology
Volume20
Issue number10
Early online date16 Sept 2019
DOIs
Publication statusPublished - 1 Oct 2019

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