Targeting eIF5A Hypusination Prevents Anoxic Cell Death through Mitochondrial Silencing and Improves Kidney Transplant Outcome

• Published in: Journal of the American Society of Nephrology 2017-03, Vol.28 (3), p.811-822
• Main Authors: Melis, Nicolas, Rubera, Isabelle, Cougnon, Marc, Giraud, Sébastien, Mograbi, Baharia, Belaid, Amine, Pisani, Didier F, Huber, Stephan M, Lacas-Gervais, Sandra, Fragaki, Konstantina, Blondeau, Nicolas, Vigne, Paul, Frelin, Christian, Hauet, Thierry, Duranton, Christophe, Tauc, Michel
• Format: Article
• Language: English
• Subjects: Animals; Basic Research; Cell Death; Cell Death - drug effects; Cell Hypoxia; Cell Hypoxia - drug effects; Cells, Cultured; Cellular Biology; Eukaryotic Translation Initiation Factor 5A; Female; Human health and pathology; Kidney Transplantation; Life Sciences; Lysine; Lysine - analogs & derivatives; Lysine - pharmacology; Male; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria - drug effects; Mitochondria - physiology; Mixed Function Oxygenases; Peptide Initiation Factors; Peptide Initiation Factors - drug effects; Pharmaceutical sciences; Pharmacology; Rats; Rats, Wistar; RNA-Binding Proteins; RNA-Binding Proteins - drug effects; Subcellular Processes; Swine; Treatment Outcome; Urology and Nephrology
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2016010012

The eukaryotic initiation factor 5A (eIF5A), which is highly conserved throughout evolution, has the unique characteristic of post-translational activation through hypusination. This modification is catalyzed by two enzymatic steps involving deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). Notably, eIF5A may be involved in regulating the lifespan of during long-term hypoxia. Therefore, we investigated the possibility of a link between eIF5A hypusination and cellular resistance to hypoxia/anoxia. Pharmacologic targeting of DHPS by 1-guanyl-1,7-diaminoheptane (GC7) or RNA interference-mediated inhibition of DHPS or DOHH induced tolerance to anoxia in immortalized mouse renal proximal cells. Furthermore, GC7 treatment of cells reversibly induced a metabolic shift toward glycolysis as well as mitochondrial remodeling and led to downregulated expression and activity of respiratory chain complexes, features characteristic of mitochondrial silencing. GC7 treatment also attenuated anoxia-induced generation of reactive oxygen species in these cells and in normoxic conditions, decreased the mitochondrial oxygen consumption rate of cultured cells and mice. In rats, intraperitoneal injection of GC7 substantially reduced renal levels of hypusinated eIF5A and protected against ischemia-reperfusion-induced renal injury. Finally, in the preclinical pig kidney transplant model, intravenous injection of GC7 before kidney removal significantly improved graft function recovery and late graft function and reduced interstitial fibrosis after transplant. This unconventional signaling pathway offers an innovative therapeutic target for treating hypoxic-ischemic human diseases and organ transplantation.