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

Nature immunology (2019-09-19)
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone, ≥98% (TLC), powder
Sigma-Aldrich
2-Deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-D-glucose, ≥97% (HPLC)
Sigma-Aldrich
Allyl methyl sulfone, 96%
Sigma-Aldrich
MISSION® esiRNA, targeting human SDHA

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