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

Research output: Contribution to journalArticlepeer-review


  • 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
  • J Lotscher
  • U 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

Colleges, School and Institutes

External organisations

  • University of Basel
  • Univ Basel
  • McGill Univ
  • Goodman Cancer Research Centre
  • Department of Physiology and Pharmacology, Molecular Exercise Physiology Research Group, Karolinska Institutet
  • McGill University
  • Univ Zurich Hosp


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
Issue number10
Early online date16 Sep 2019
Publication statusPublished - 1 Oct 2019