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

Authors
  • Ko, Jeong-Hun1
  • Olona, Antoni1
  • Papathanassiu, Adonia E2
  • Buang, Norzawani1
  • Park, Kwon-Sik3
  • Costa, Ana S H4
  • Mauro, Claudio5
  • Frezza, Christian4
  • Behmoaras, Jacques6
  • 1 Centre for Inflammatory Disease, Imperial College London, London W12 0NN, UK.
  • 2 Ergon Pharmaceuticals, LLC, P.O. Box 1001, Silver Spring, MD 20910, USA [email protected] [email protected]
  • 3 Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
  • 4 Medical Research Council Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK.
  • 5 Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Mindelsohn Way, Birmingham B15 2WB, UK.
  • 6 Centre for Inflammatory Disease, Imperial College London, London W12 0NN, UK [email protected] [email protected]
Type
Published Article
Journal
Journal of Cell Science
Publisher
The Company of Biologists
Publication Date
Nov 27, 2020
Volume
133
Issue
22
Identifiers
DOI: 10.1242/jcs.247957
PMID: 33148611
Source
Medline
Keywords
Language
English
License
Unknown

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 remains 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 uptake of BCAAs is not altered, their transamination by BCAT1 is increased following 8 h lipopolysaccharide (LPS) stimulation. Of note, leucine is not metabolized to integrate into the TCA cycle in basal or 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 the TCA cycle. This indirect effect is associated with NRF2 (also known as NFE2L2) activation and anti-oxidant responses. These results suggest a moonlighting role of BCAT1 through redox-mediated control of mitochondrial function during early macrophage activation. © 2020. Published by The Company of Biologists Ltd.

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