The RNA-Binding Protein PUM2 Impairs Mitochondrial Dynamics and Mitophagy During Aging
Open accessAbstract
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 lifespan 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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Specific deletion of PUM2 in old mice's skeletal muscle increases MFF levels, enhances mitochondrial fission and mitophagy, and improves mitochondrial function and lifespan.
“Accordingly, the specific deletion of PUM2 in old mice's skeletal muscle increases MFF levels, enhances mitochondrial fission and mitophagy, and improves mitochondrial function and lifespan [119].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [119]
Rebalancing of mitochondrial dynamics rescues the phenotype of certain diseases associated with alterations of mitochondrial fusion or fission.
“Several reports have shown that rebalancing of mitochondrial dynamics rescues the phenotype of certain diseases associated with alterations of mitochondrial fusion or fission [119, 194, 195, 214]”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [119]
PUM2 binds and represses specifically the translation of MFF mRNA.
“The RNA-binding protein PUM2 binds and represses, specifically the translation of MFF mRNA [119].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [119]
PUM2 levels increase with age in worms, mice, and humans, while MFF is reduced upon aging, suggesting that abnormal mitochondrial fission and mitophagy contribute to age-related sarcopenia.
“PUM2 levels increase with age in worms, mice and humans, while MFF is reduced upon aging, suggesting that abnormal mitochondrial fission and mitophagy contribute to age-related sarcopenia.”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [119]
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- Authors
- D’Amico, D., Mottis, A., Potenza, F., Sorrentino, V., Li, H., Romani, M., Lemos, V., Schoonjans, K., Zamboni, N., Knott, G., Schneider, B. L., & Auwerx, J.
- Affiliations
- École Polytechnique Fédérale de Lausanne (CH)
- ETH Zurich (CH)
- Corresponding author
- Auwerx, Johan
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2019-02
- Volume
- 73
- Issue
- 4
- Pages
- 775-787.e10
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC6396316
- OpenAlex
- W2908940327
- Cited by
- 159
- References
- 79
- Citations by year
- 2026: 12 · 2025: 18 · 2024: 22 · 2023: 31 · 2022: 17 · 2021: 25 · 2020: 21 · 2019: 12
- FWCI
- 6.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (acceptedVersion, cc-by)
- PubMed Central (acceptedVersion)
- National University of Singapore (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Funders
- Associazione Italiana per la Ricerca sul Cancro
- Marie Curie Actions
- EPFL Fellows
- Marie Skłodowska-Curie Horizon 2020 (665667)
- EPFL
- NIH (R01AG043930)
- Systems X (SySX.ch 2013/153)
- Velux Stiftung (1019)
- FSRMM
- SNSF (310030B_160318, 31003A_179435)
- Fondation Levaillant
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- PUM2
- MeSH terms
- Age Factors, Aging, Animals, Female, HeLa Cells, Humans, Male, Membrane Proteins, Mice, Inbred C57BL, Mitochondria, Mitochondria, Muscle, Signal Transduction, Up-Regulation, RNA-Binding Proteins, Caenorhabditis elegans, Muscle, Skeletal, Mitochondrial Proteins, Caenorhabditis elegans Proteins, HEK293 Cells, Mitochondrial Dynamics, Mitophagy
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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