Targeting eIF5A Hypusination Prevents Anoxic Cell Death through Mitochondrial Silencing and Improves Kidney Transplant Outcome.
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 ofDrosophiladuring long-term hypoxia. Therefore, we investigated the possibility of a link between eIF5A hypusination and cellular resistance to hypoxia/anoxia. Pharmacologic targeting of DHPS byN1-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.
Laboratoire de Physio-Médecine Moléculaire, Centre National de la Recherche Scientifique-UMR7370.
Nicolas
N
Melis
Laboratoire de Physio-Médecine Moléculaire, Centre National de la Recherche Scientifique-UMR7370.
Isabelle
I
Rubera
Laboratoire de Physio-Médecine Moléculaire, Centre National de la Recherche Scientifique-UMR7370.
Marc
M
Cougnon
Centre Hospitalo Universitaire Poitiers, Service de Biochimie, Poitiers, France.|Institut National de la Santé et de la Recherche Médicale U1082 Ischémie Reperfusion en Transplantation d'Organes Mécanismes et Innovations Thérapeutiques, Poitiers, France.|Faculté de Médecine et de Pharmacie, Université de Poitiers, Poitiers, France; and.
Sébastien
S
Giraud
Institut de Recherche sur le Cancer, Centre National de la Recherche Scientifique-UMR7284, Institut National de la Santé et de la Recherche Médicale U1081.
Baharia
B
Mograbi
Institut de Recherche sur le Cancer, Centre National de la Recherche Scientifique-UMR7284, Institut National de la Santé et de la Recherche Médicale U1081.
Amine
A
Belaid
Institute of Biology Valrose, Centre National de la Recherche Scientifique-UMR7277 Institut National de la Santé et de la Recherche Médicale U1091.
Didier F
DF
Pisani
Department of Radiation Oncology, University of Tübingen, Tuebingen, Germany.
Stephan M
SM
Huber
Centre Commun de Microscopie Appliquée, and.
Sandra
S
Lacas-Gervais
Institut de Recherche sur le Cancer, Centre National de la Recherche Scientifique-UMR7284, Institut National de la Santé et de la Recherche Médicale U1081.
Konstantina
K
Fragaki
Institut de Physiologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique Unité Mixte de Recherche UMR7275, University Nice-Sophia Antipolis, Nice, France.
Nicolas
N
Blondeau
Institute of Biology Valrose, Centre National de la Recherche Scientifique-UMR7277 Institut National de la Santé et de la Recherche Médicale U1091.
Paul
P
Vigne
Institute of Biology Valrose, Centre National de la Recherche Scientifique-UMR7277 Institut National de la Santé et de la Recherche Médicale U1091.
Christian
C
Frelin
Centre Hospitalo Universitaire Poitiers, Service de Biochimie, Poitiers, France.|Institut National de la Santé et de la Recherche Médicale U1082 Ischémie Reperfusion en Transplantation d'Organes Mécanismes et Innovations Thérapeutiques, Poitiers, France.|Faculté de Médecine et de Pharmacie, Université de Poitiers, Poitiers, France; and.
Thierry
T
Hauet
Laboratoire de Physio-Médecine Moléculaire, Centre National de la Recherche Scientifique-UMR7370.
Christophe
C
Duranton
Laboratoire de Physio-Médecine Moléculaire, Centre National de la Recherche Scientifique-UMR7370, michel.tauc@unice.fr.
Michel
M
Tauc
D000818:Animals; D016923:Cell Death / Q000187:drug effects*; D015687:Cell Hypoxia / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D016030:Kidney Transplantation; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology*; D006899:Mixed Function Oxygenases; D010448:Peptide Initiation Factors / Q000187:drug effects*; D016601:RNA-Binding Proteins / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013552:Swine; D016896:Treatment Outcome; D000097574:Eukaryotic Translation Initiation Factor 5A
D008239:Lysine; D006899:Mixed Function Oxygenases; D010448:Peptide Initiation Factors; D016601:RNA-Binding Proteins; D000097574:Eukaryotic Translation Initiation Factor 5A; C100028:hypusine; C047991:deoxyhypusine hydroxylase
cell survival; hypoxia; ischemia; kidney transplantation; renal cell biology; transplant outcomes