期刊
MOLECULAR CELL
卷 73, 期 4, 页码 775-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2018.11.034
关键词
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资金
- Associazione Italiana per la Ricerca sul Cancro (AIRC)
- Marie Curie Actions
- EPFL Fellows program - Marie Sklodowska-Curie Horizon 2020 [665667]
- EPFL
- NIH [R01AG043930]
- Velux Stiftung [1019]
- FSRMM
- SNSF [310030B_160318, 31003A_179435]
- Fondation Levaillant
- Systems X [SySX.ch 2013/153]
- Swiss National Science Foundation (SNF) [310030B_160318] Funding Source: Swiss National Science Foundation (SNF)
Little information is available about how post-transcriptional mechanisms regulate the aging process. Here, we show that the RNA-binding protein Pumilio2 (PUM2), which is a translation repressor, is induced upon aging and acts as a negative regulator of life span and mitochondrial homeostasis. Multi-omics and cross-species analyses of PUM2 function show that it inhibits the translation of the mRNA encoding for the mitochondrial fission factor (Mff), thereby impairing mitochondrial fission and mitophagy. This mechanism is conserved in C. elegans by the PUM2 ortholog PUF-8. puf-8 knock-down in old nematodes and Pum2 CRISPR/Cas9-mediated knockout in the muscles of elderly mice enhances mitochondrial fission and mitophagy in both models, hence improving mitochondrial quality control and tissue homeostasis. Our data reveal how a PUM2-mediated layer of post-transcriptional regulation links altered Mff translation to mitochondrial dynamics and mitophagy, thereby mediating age related mitochondrial dysfunctions.
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