[HTML][HTML] Foxp3 drives oxidative phosphorylation and protection from lipotoxicity

D Howie, SP Cobbold, E Adams, A Ten Bokum… - JCI insight, 2017 - ncbi.nlm.nih.gov
D Howie, SP Cobbold, E Adams, A Ten Bokum, AS Necula, W Zhang, H Huang, DJ Roberts
JCI insight, 2017ncbi.nlm.nih.gov
Tregs can adopt a catabolic metabolic program with increased capacity for fatty acid
oxidation–fueled oxidative phosphorylation (OXPHOS). It is unclear why this form of
metabolism is favored in Tregs and, more specifically, whether this program represents an
adaptation to the environment and developmental cues or is “hardwired” by Foxp3. Here we
show, using metabolic analysis and an unbiased mass spectroscopy–based proteomics
approach, that Foxp3 is both necessary and sufficient to program Treg-increased respiratory …
Abstract
Tregs can adopt a catabolic metabolic program with increased capacity for fatty acid oxidation–fueled oxidative phosphorylation (OXPHOS). It is unclear why this form of metabolism is favored in Tregs and, more specifically, whether this program represents an adaptation to the environment and developmental cues or is “hardwired” by Foxp3. Here we show, using metabolic analysis and an unbiased mass spectroscopy–based proteomics approach, that Foxp3 is both necessary and sufficient to program Treg-increased respiratory capacity and Tregs’ increased ability to utilize fatty acids to fuel oxidative phosphorylation. Foxp3 drives upregulation of components of all the electron transport complexes, increasing their activity and ATP generation by oxidative phosphorylation. Increased fatty acid β-oxidation also results in selective protection of Foxp3+ cells from fatty acid–induced cell death. This observation may provide novel targets for modulating Treg function or selection therapeutically.
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