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<p>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 (<i>MRPP3)</i> mRNA encoding a protein essential for mitochondrial tRNA (mt-tRNA) maturation. We show that eIF5A<sup>hyp</sup> regulates the nuclear export of <i>MRPP3</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月13日

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

摘要

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 (eIF5Ahyp) promotes metastasis and tumor growth in prostate cancer (PCa) by supporting mitochondrial metabolism and translation. eIF5Ahyp 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 eIF5Ahyp 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 eIF5Ahyp. Together, we uncover a critical role for eIF5Ahyp in mitochondrial protein synthesis and highlight its broader implications in coordinating the expression of nuclear and mitochondrial genomes, linking hypusination to cancer progression.