Format

Send to

Choose Destination
Mol Cell. 2019 Jan 11. pii: S1097-2765(18)31004-9. doi: 10.1016/j.molcel.2018.11.034. [Epub ahead of print]

The RNA-Binding Protein PUM2 Impairs Mitochondrial Dynamics and Mitophagy During Aging.

Author information

1
Laboratory for Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
2
Laboratory of Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015, Lausanne, Switzerland.
3
Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule Zürich (ETHZ), CH-8093, Zurich, Switzerland.
4
BioEM Facility, Faculty of Life Sciences Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
5
Brain Mind Insitute, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
6
Laboratory for Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland. Electronic address: admin.auwerx@epfl.ch.

Abstract

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.

KEYWORDS:

RNA binding proteins; aging; fission/fusion; mitochondria; mitochondrial dynamics; mitophagy; neurodegeneration; protein aggregation diseases; proteostasis; ribonucleoprotein granules

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center