Polyamines and eIF5A Hypusination Modulate Mitochondrial Respiration and Macrophage Activation

Cell Metab. 2019 Aug 6;30(2):352-363.e8. doi: 10.1016/j.cmet.2019.05.003. Epub 2019 May 23.


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: deoxyhypusine hydroxylase; deoxyhypusine synthase; eIF5A; hypusination; immunometabolism; macrophage activation; metabolism; polyamines.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Macrophage Activation
  • Macrophages / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondria / metabolism*
  • Peptide Initiation Factors / metabolism*
  • Polyamines / metabolism*
  • Proteomics
  • RNA-Binding Proteins / metabolism*


  • Peptide Initiation Factors
  • Polyamines
  • RNA-Binding Proteins
  • eukaryotic translation initiation factor 5A