Kantonsspital St.Gallen
login

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

Anne-Valérie Burgener, Glenn R Bantug, Benedikt J Meyer, Rebecca Higgins, Adhideb Ghosh, Olivier Bignucolo, Eric H Ma, Jordan Loeliger, Gunhild Unterstab, Marco Geigges, Rebekah Steiner, Michel Enamorado, Robert Ivanek, Danielle Hunziker, Alexander Schmidt, Bojana Müller-Durovic, Jasmin Grählert, Raja Epple, Sarah Dimeloe, Jonas Lötscher, Ursula Sauder, Monika Ebnöther, Bettina Burger, Ingmar Heijnen, Sarai Martínez-Cano, Nathan Cantoni, Rolf Brücker, Christian R. Kahlert, David Sancho, Russell G Jones, Alexander Navarini, Mike Recher & Christoph Hess

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.
   
citation Burgener A V, Bantug G R, Meyer B J, Higgins R, Ghosh A, Bignucolo O, Ma E H, Loeliger J, Unterstab G, Geigges M, Steiner R, Enamorado M, Ivanek R, Hunziker D, Schmidt A, Müller-Durovic B, Grählert J, Epple R, Dimeloe S, Lötscher J, Sauder U, Ebnöther M, Burger B, Heijnen I, Martínez-Cano S, Cantoni N, Brücker R, Kahlert C R, Sancho D, Jones R G, Navarini A, Recher M, 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)
date of publishing 16-09-2019
journal title Nat Immunol (20/10)
ISSN electronic 1529-2916
pages 1311-1321
PubMed 31527833
DOI 10.1038/s41590-019-0482-2