Publication

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

Journal Paper/Review - Sep 16, 2019

Units
PubMed
Doi

Citation
Burgener A, Dimeloe S, Lötscher J, Sauder U, Ebnöther M, Burger B, Heijnen I, Martínez-Cano S, Cantoni N, Brücker R, Kahlert C, Sancho D, Jones R, Navarini A, Recher M, Epple R, Grählert J, Müller-Durovic B, 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 A, Hess C. SDHA gain-of-function engages inflammatory mitochondrial retrograde signaling via KEAP1-Nrf2. Nat Immunol 2019; 20:1311-1321.
Type
Journal Paper/Review (English)
Journal
Nat Immunol 2019; 20
Publication Date
Sep 16, 2019
Issn Electronic
1529-2916
Pages
1311-1321
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.