bims-hypusi 2024-08-11 papers

Issue of 2024‒08‒11
two papers selected by
Sebastian J. Hofer, University of Graz

Nat Cell Biol. 2024 Aug 08.

Spermidine is essential for fasting-mediated autophagy and longevity.

Sebastian J Hofer, Ioanna Daskalaki, Martina Bergmann, Jasna Friščić, Andreas Zimmermann, Melanie I Mueller, Mahmoud Abdellatif, Raffaele Nicastro, Sarah Masser, Sylvère Durand, Alexander Nartey, Mara Waltenstorfer, Sarah Enzenhofer, Isabella Faimann, Verena Gschiel, Thomas Bajaj, Christine Niemeyer, Ilias Gkikas, Lukas Pein, Giulia Cerrato, Hui Pan, YongTian Liang, Jelena Tadic, Andrea Jerkovic, Fanny Aprahamian, Christine E Robbins, Nitharsshini Nirmalathasan, Hansjörg Habisch, Elisabeth Annerer, Frederik Dethloff, Michael Stumpe, Franziska Grundler, Françoise Wilhelmi de Toledo, Daniel E Heinz, Daniela A Koppold, Anika Rajput Khokhar, Andreas Michalsen, Norbert J Tripolt, Harald Sourij, Thomas R Pieber, Rafael de Cabo, Mark A McCormick, Christoph Magnes, Oliver Kepp, Joern Dengjel, Stephan J Sigrist, Nils C Gassen, Simon Sedej, Tobias Madl, Claudio De Virgilio, Ulrich Stelzl, Markus H Hoffmann, Tobias Eisenberg, Nektarios Tavernarakis, Guido Kroemer, Frank Madeo.

Caloric restriction and intermittent fasting prolong the lifespan and healthspan of model organisms and improve human health. The natural polyamine spermidine has been similarly linked to autophagy enhancement, geroprotection and reduced incidence of cardiovascular and neurodegenerative diseases across species borders. Here, we asked whether the cellular and physiological consequences of caloric restriction and fasting depend on polyamine metabolism. We report that spermidine levels increased upon distinct regimens of fasting or caloric restriction in yeast, flies, mice and human volunteers. Genetic or pharmacological blockade of endogenous spermidine synthesis reduced fasting-induced autophagy in yeast, nematodes and human cells. Furthermore, perturbing the polyamine pathway in vivo abrogated the lifespan- and healthspan-extending effects, as well as the cardioprotective and anti-arthritic consequences of fasting. Mechanistically, spermidine mediated these effects via autophagy induction and hypusination of the translation regulator eIF5A. In summary, the polyamine-hypusination axis emerges as a phylogenetically conserved metabolic control hub for fasting-mediated autophagy enhancement and longevity.

DOI: https://doi.org/10.1038/s41556-024-01468-x

Clin Transl Med. 2024 Aug;14(8): e1791

Oocyte-specific deletion of eukaryotic translation initiation factor 5 causes apoptosis of mouse oocytes within the early-growing follicles by mitochondrial fission defect-reactive oxygen species-DNA damage.

Weiyong Wang, Huiyu Liu, Shuang Liu, Tiantian Hao, Ying Wei, Hongwei Wei, Wenjun Zhou, Xiaodan Zhang, Xiaoqiong Hao, Meijia Zhang.

BACKGROUND: Mutations in several translation initiation factors are closely associated with premature ovarian insufficiency (POI), but the underlying pathogenesis remains largely unknown.METHODS AND RESULTS: We generated eukaryotic translation initiation factor 5 (Eif5) conditional knockout mice aiming to investigate the function of eIF5 during oocyte growth and follicle development. Here, we demonstrated that Eif5 deletion in mouse primordial and growing oocytes both resulted in the apoptosis of oocytes within the early-growing follicles. Further studies revealed that Eif5 deletion in oocytes downregulated the levels of mitochondrial fission-related proteins (p-DRP1, FIS1, MFF and MTFR) and upregulated the levels of the integrated stress response-related proteins (AARS1, SHMT2 and SLC7A1) and genes (Atf4, Ddit3 and Fgf21). Consistent with this, Eif5 deletion in oocytes resulted in mitochondrial dysfunction characterized by elongated form, aggregated distribution beneath the oocyte membrane, decreased adenosine triphosphate content and mtDNA copy numbers, and excessive accumulation of reactive oxygen species (ROS) and mitochondrial superoxide. Meanwhile, Eif5 deletion in oocytes led to a significant increase in the levels of DNA damage response proteins (γH2AX, p-CHK2 and p-p53) and proapoptotic proteins (PUMA and BAX), as well as a significant decrease in the levels of anti-apoptotic protein BCL-xL.
CONCLUSION: These findings indicate that Eif5 deletion in mouse oocytes results in the apoptosis of oocytes within the early-growing follicles via mitochondrial fission defects, excessive ROS accumulation and DNA damage. This study provides new insights into pathogenesis, genetic diagnosis and potential therapeutic targets for POI.
KEY POINTS: Eif5 deletion in oocytes leads to arrest in oocyte growth and follicle development. Eif5 deletion in oocytes impairs the translation of mitochondrial fission-related proteins, followed by mitochondrial dysfunction. Depletion of Eif5 causes oocyte apoptosis via ROS accumulation and DNA damage response pathway.

Keywords: POI; eIF5; follicle development; mitochondrial fission; oocyte growth

DOI: https://doi.org/10.1002/ctm2.1791