Polyamines and eIF5A Hypusination Modulate Mitochondrial Respiration and Macrophage Activation

• Published in: Cell metabolism Vol. 30; no. 2; pp. 352 - 363.e8
• Main Authors: Puleston, Daniel J., Buck, Michael D., Klein Geltink, Ramon I., Kyle, Ryan L., Caputa, George, O’Sullivan, David, Cameron, Alanna M., Castoldi, Angela, Musa, Yaarub, Kabat, Agnieszka M., Zhang, Ying, Flachsmann, Lea J., Field, Cameron S., Patterson, Annette E., Scherer, Stefanie, Alfei, Francesca, Baixauli, Francesc, Austin, S. Kyle, Kelly, Beth, Matsushita, Mai, Curtis, Jonathan D., Grzes, Katarzyna M., Villa, Matteo, Corrado, Mauro, Sanin, David E., Qiu, Jing, Pällman, Nora, Paz, Katelyn, Maccari, Maria Elena, Blazar, Bruce R., Mittler, Gerhard, Buescher, Joerg M., Zehn, Dietmar, Rospert, Sabine, Pearce, Edward J., Balabanov, Stefan, Pearce, Erika L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.08.2019; Cell Press
• Subjects: Animals; Cells, Cultured; deoxyhypusine hydroxylase; deoxyhypusine synthase; eIF5A; Eukaryotic Translation Initiation Factor 5A; hypusination; immunometabolism; Macrophage Activation; Macrophages - metabolism; metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria - metabolism; Peptide Initiation Factors - metabolism; polyamines; Polyamines - metabolism; Proteomics; RNA-Binding Proteins - metabolism; hypusination; immunometabolism; deoxyhypusine hydroxylase; metabolism; macrophage activation; deoxyhypusine synthase; polyamines; eIF5A
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2019.05.003

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. [Display omitted] •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 Puleston et al. show that polyamine biosynthesis modulates mitochondrial metabolism through eIF5A hypusination (eIF5AH). They find that inhibiting the polyamine-eIF5A-hypusine pathway blocks OXPHOS-dependent macrophage alternative activation, while leaving aerobic glycolysis-dependent macrophage classical activation intact. These results might have implications for therapeutically controlling macrophage activation by targeting the polyamine-eIF5A-hypusine axis.