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

被引：149

作者：

D'Amico, Davide ^{[1
]}

Mottis, Adrienne ^{[1
]}

Potenza, Francesca ^{[1
]}

Sorrentino, Vincenzo ^{[1
]}

Li, Hao ^{[1
]}

Romani, Mario ^{[1
]}

Lemos, Vera ^{[2
]}

Schoonjans, Kristina ^{[2
]}

Zamboni, Nicola ^{[3
]}

Knott, Graham ^{[4
]}

Schneider, Bernard L. ^{[5
]}

Auwerx, Johan ^{[1
]}

机构：

[1] Ecole Polytech Fed Lausanne, Inst Bioengn, Lab Integrat & Syst Physiol, CH-1015 Lausanne, Switzerland

[2] Ecole Polytech Fed Lausanne, Lab Metab Signaling, Inst Bioengn, CH-1015 Lausanne, Switzerland

[3] ETHZ, Dept Biol, Inst Mol Syst Biol, CH-8093 Zurich, Switzerland

[4] Ecole Polytech Fed Lausanne, Fac Life Sci, BioEM Facil, CH-1015 Lausanne, Switzerland

[5] Ecole Polytech Fed Lausanne, Brain Mind Inst, CH-1015 Lausanne, Switzerland

来源：

MOLECULAR CELL | 2019年 / 73卷 / 04期

基金：

欧盟地平线“2020”; 瑞士国家科学基金会;

关键词：

PRION-LIKE DOMAINS; GENE-EXPRESSION; LIFE-SPAN; GENOMIC STABILITY; SKELETAL-MUSCLE; C-ELEGANS; STRESS; FISSION; AGE; IDENTIFICATION;

D O I：

10.1016/j.molcel.2018.11.034

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：775 / +

页数：23

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