BCAT1 affects mitochondrial metabolism independently of leucine transamination in activated human macrophages

Research output: Contribution to journalArticlepeer-review

Authors

  • Jeong-Hun Ko
  • Antoni Olona
  • Adonia E Papathanassiu
  • Norzawani Buang
  • Kwon-Sik Park
  • Ana S H Costa
  • Christian Frezza
  • Jacques Behmoaras

External organisations

  • Imperial College London
  • Ergon Pharmaceuticals
  • University of Virginia School of Medicine
  • Cancer Research UK Cambridge Institute
  • Institute for Inflammation and Ageing
  • Birmingham Women's and Children's Hospital NHS Foundation Trust

Abstract

In response to environmental stimuli, macrophages change their nutrient consumption and undergo an early metabolic adaptation that progressively shapes their polarization state. During the transient, early phase of pro-inflammatory macrophage activation, an increase in tricarboxylic acid (TCA) cycle activity has been reported but the relative contribution of branched chain amino acid (BCAA) leucine remain to be determined. Here we show that glucose but not glutamine is a major contributor of the increase in TCA cycle metabolites during early macrophage activation in humans. We then show that, although BCAA uptake is not altered, their transamination by BCAT1 is increased following 8h lipopolysaccharide (LPS) stimulation. Of note, leucine is not metabolized to integrate the TCA cycle in neither basal nor stimulated human macrophages. Surprisingly, the pharmacological inhibition of BCAT1 reduced glucose-derived itaconate, α-ketoglutarate, and 2-hydroxyglutarate levels, without affecting succinate and citrate levels, indicating a partial inhibition of TCA cycle. This indirect effect is associated with NRF2 activation and anti-oxidant responses. These results suggest a moonlighting role of BCAT1 through redox-mediated control of mitochondrial function during early macrophage activation.

Details

Original languageEnglish
JournalJournal of Cell Science
Publication statusE-pub ahead of print - 12 Nov 2020