Cell Metabolism
Volume 30, Issue 2, 6 August 2019, Pages 352-363.e8
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Short Article
Polyamines and eIF5A Hypusination Modulate Mitochondrial Respiration and Macrophage Activation

https://doi.org/10.1016/j.cmet.2019.05.003Get rights and content
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Highlights

  • The polyamine synthesis pathway and hypusinated eIF5A modulate mitochondrial OXPHOS

  • Hypusinated eIF5A maintains TCA cycle and ETC integrity in macrophages

  • Some mitochondrial enzymes depend on eIF5AH for efficient expression

  • Inhibition of hypusinated eIF5A blunts macrophage alternative activation

Summary

How cells adapt metabolism to meet demands is an active area of interest across biology. Among a broad range of functions, the polyamine spermidine is needed to hypusinate the translation factor eukaryotic initiation factor 5A (eIF5A). We show here that hypusinated eIF5A (eIF5AH) promotes the efficient expression of a subset of mitochondrial proteins involved in the TCA cycle and oxidative phosphorylation (OXPHOS). Several of these proteins have mitochondrial targeting sequences (MTSs) that in part confer an increased dependency on eIF5AH. In macrophages, metabolic switching between OXPHOS and glycolysis supports divergent functional fates stimulated by activation signals. In these cells, hypusination of eIF5A appears to be dynamically regulated after activation. Using in vivo and in vitro models, we show that acute inhibition of this pathway blunts OXPHOS-dependent alternative activation, while leaving aerobic glycolysis-dependent classical activation intact. These results might have implications for therapeutically controlling macrophage activation by targeting the polyamine-eIF5A-hypusine axis.

Keywords

immunometabolism
hypusination
eIF5A
deoxyhypusine synthase
deoxyhypusine hydroxylase
macrophage activation
metabolism
polyamines

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These authors contributed equally

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