Hypusination of the translation factor eIF5A regulates mitochondrial tRNA processing to promote prostate cancer aggressiveness

Protein synthesis plays a central role in cancer development and progression. eukaryotic initiation factor 5 A (eIF5A), a translation factor activated by hypusination, is implicated in tumorigenesis, however, its mode of action is still unclear. We find that hypusinated eIF5A (eIF5A<sup>hyp</sup>) promotes metastasis and tumor growth in prostate cancer (PCa) by supporting mitochondrial metabolism and translation. eIF5A<sup>hyp</sup> controls the subcellular localization of Mitochondrial Ribonuclease P Protein 3 (MRPP3) mRNA encoding a protein essential for mitochondrial tRNA (mt-tRNA) maturation. We show that eIF5A<sup>hyp</sup> regulates the nuclear export of MRPP3 mRNA, its expression, thereby promoting mt-tRNA maturation. Our findings establish that MRPP3 enhances mitochondrial metabolism and supports PCa metastasis. Importantly, its expression restores mitochondrial translation and tumor growth inhibited by the downregulation of eIF5A<sup>hyp</sup>. Together, we uncover a critical role for eIF5A<sup>hyp</sup> in mitochondrial protein synthesis and highlight its broader implications in coordinating the expression of nuclear and mitochondrial genomes, linking hypusination to cancer progression.

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Journal
Nature Communications
Published
2026-03-13
DOI
https://doi.org/10.1038/s41467-026-70566-1
Primary Topic
Polyamine Metabolism and Applications
Type
article
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0.00

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article

Hypusination of the translation factor eIF5A regulates mitochondrial tRNA processing to promote prostate cancer aggressiveness

M. Durand, Stéphane Audebert, Loïc Trapani, Pascal Peraldi et al.
Nature Communications
Polyamine Metabolism and Applications
article

Hypusination of the translation factor eIF5A regulates mitochondrial tRNA processing to promote prostate cancer aggressiveness

M. Durand, Stéphane Audebert, Loïc Trapani, Pascal Peraldi, Joseph Murdaca, Jean‐Jacques Diaz, Paraskevi Kousteridou, Luc Camoin, Nathalie M. Mazure, Heather S. Carr, Michel Kahi, Arnaud Jacquel, Victor Tiroille, Émilie Baudelet, Amine Belaïd, Frédéric Bost, Frédéric Larbret, Didier F. Pisani, Marie Irondelle, Ludovic Batistic, Damien Ambrosetti, Oumayma Benaceur, Christelle Boscagli, Issam Ben-Sahra, Abigail Mazzu′, Mathieu Carlier, Silvère Baron, Emilie Thomas, Anne Vincent, Pierre Bertrand, Yu Chen, Marc Pujalte-Martin
article en

Abstract

Protein synthesis plays a central role in cancer development and progression. eukaryotic initiation factor 5 A (eIF5A), a translation factor activated by hypusination, is implicated in tumorigenesis, however, its mode of action is still unclear. We find that hypusinated eIF5A (eIF5A<sup>hyp</sup>) promotes metastasis and tumor growth in prostate cancer (PCa) by supporting mitochondrial metabolism and translation. eIF5A<sup>hyp</sup> controls the subcellular localization of Mitochondrial Ribonuclease P Protein 3 (MRPP3) mRNA encoding a protein essential for mitochondrial tRNA (mt-tRNA) maturation. We show that eIF5A<sup>hyp</sup> regulates the nuclear export of MRPP3 mRNA, its expression, thereby promoting mt-tRNA maturation. Our findings establish that MRPP3 enhances mitochondrial metabolism and supports PCa metastasis. Importantly, its expression restores mitochondrial translation and tumor growth inhibited by the downregulation of eIF5A<sup>hyp</sup>. Together, we uncover a critical role for eIF5A<sup>hyp</sup> in mitochondrial protein synthesis and highlight its broader implications in coordinating the expression of nuclear and mitochondrial genomes, linking hypusination to cancer progression.

Nature Communications
Université Claude Bernard Lyon 1 (FR), Northwestern University (US), Centre National de la Recherche Scientifique (FR), Memorial Sloan Kettering Cancer Center (US), Inserm (FR), Université Côte d'Azur (FR), Centre Hospitalier Universitaire de Nice (FR), Laboratoire de PhysioMédecine Moléculaire (FR), University of Clermont Auvergne (FR), Hubrecht Institute for Developmental Biology and Stem Cell Research (NL), Centre Méditerranéen de Médecine Moléculaire (FR), Institut de Recherche sur le Cancer et le Vieillissement de Nice (FR), Centre de Recherche en Cancérologie de Lyon (FR), Hôpital Pasteur (FR), Clermont Université (FR), Cognition Behaviour Technology (FR), Centre de Recherche en Cancérologie de Marseille (FR), Institute of Bioinformatics (IN), Institut Paoli-Calmettes (FR), Centre Antoine Lacassagne (FR), Bose (United States) (US)
Northwestern University, Infrastructures en Biologie Santé et Agronomie, Institut National de la Santé et de la Recherche Médicale, Fondation ARC pour la Recherche sur le Cancer, Ligue Contre le Cancer, Centre National de la Recherche Scientifique, Institut National Du Cancer, Direction Générale de l’offre de Soins, Association pour la Recherche sur les Tumeurs de la Prostate, National Institutes of Health, Robert H. Lurie Comprehensive Cancer Center, National Cancer Institute
Good health and well-being
Openalex Percentile: Top 25%
Polyamine Metabolism and Applications
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