SDHA gain-of-function engages inflammatory mitochondrial retrograde signaling via KEAP1-Nrf2.
Bantug, Glenn R
Meyer, Benedikt J
Ma, Eric H
Jones, Russell G
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Burgener, A., Bantug, G. R., Meyer, B. J., Higgins, R., Ghosh, A., Bignucolo, O., Ma, E. H., et al. (2019). SDHA gain-of-function engages inflammatory mitochondrial retrograde signaling via KEAP1-Nrf2.. Nature immunology, 20 (10), 1311-1321. https://doi.org/10.1038/s41590-019-0482-2
Whether screening the metabolic activity of immune cells facilitates discovery of molecular pathology remains unknown. Here we prospectively screened the extracellular acidification rate (ECAR) as a measure of glycolysis and the oxygen consumption rate (OCR) as a measure of mitochondrial respiration in B cells from patients with primary antibody deficiency (PAD). The highest OCR 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 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 IL-6 in vivo prevented systemic inflammation and ameliorated clinical disease. Overall, our study has identified pathological mitochondrial retrograde signaling as a disease modifier in PAD.
B-Lymphocytes, Cells, Cultured, Mitochondria, Humans, Lymphocytosis, Inflammation, Fumarates, Electron Transport Complex II, Anti-Inflammatory Agents, Interleukin-6, Prospective Studies, Signal Transduction, Cell Respiration, Glycolysis, Oxygen Consumption, Mutation, NF-E2-Related Factor 2, Kelch-Like ECH-Associated Protein 1, Whole Exome Sequencing
External DOI: https://doi.org/10.1038/s41590-019-0482-2
This record's URL: https://www.repository.cam.ac.uk/handle/1810/297263
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