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

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. Aging leads to alterations in several key biological processes. However, whether and how these age-associated dysfunctions are interconnected is still poorly understood. Here, D'Amico et al. discovered that the RNA-binding protein PUM2 is induced upon aging and links impaired protein homeostasis and mitochondrial dysfunction, two well-known hallmarks of aging.