A Conserved Mito-Cytosolic Translational Balance Links Two Longevity Pathways.
Animals
Caenorhabditis elegans
/ drug effects
Caenorhabditis elegans Proteins
/ metabolism
Cytosol
/ drug effects
Doxycycline
/ pharmacology
Longevity
Mice, Inbred C57BL
Mitochondria
/ drug effects
Phenotype
Protein Biosynthesis
/ drug effects
Proteome
/ metabolism
RNA Interference
Ribosomal Proteins
/ metabolism
Signal Transduction
/ drug effects
Stress, Physiological
/ drug effects
Transcription Factors
/ metabolism
Transcriptome
/ drug effects
Up-Regulation
/ drug effects
ATF4
aging
cytosolic translation
doxycycline
longevity
mitochondrial translation
polysome
ribosomes
translational balance
translational efficiency
Journal
Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170
Informations de publication
Date de publication:
03 03 2020
03 03 2020
Historique:
received:
18
12
2018
revised:
22
08
2019
accepted:
22
01
2020
pubmed:
23
2
2020
medline:
2
7
2021
entrez:
22
2
2020
Statut:
ppublish
Résumé
Slowing down translation in either the cytosol or the mitochondria is a conserved longevity mechanism. Here, we found a non-interventional natural correlation of mitochondrial and cytosolic ribosomal proteins (RPs) in mouse population genetics, suggesting a translational balance. Inhibiting mitochondrial translation in C. elegans through mrps-5 RNAi repressed cytosolic translation. Transcriptomics integrated with proteomics revealed that this inhibition specifically reduced translational efficiency of mRNAs required in growth pathways while increasing stress response mRNAs. The repression of cytosolic translation and extension of lifespan from mrps-5 RNAi were dependent on atf-5/ATF4 and independent from metabolic phenotypes. We found the translational balance to be conserved in mammalian cells upon inhibiting mitochondrial translation pharmacologically with doxycycline. Lastly, extending this in vivo, doxycycline repressed cytosolic translation in the livers of germ-free mice. These data demonstrate that inhibiting mitochondrial translation initiates an atf-5/ATF4-dependent cascade leading to coordinated repression of cytosolic translation, which could be targeted to promote longevity.
Identifiants
pubmed: 32084377
pii: S1550-4131(20)30012-7
doi: 10.1016/j.cmet.2020.01.011
pmc: PMC7214782
mid: NIHMS1569017
pii:
doi:
Substances chimiques
Caenorhabditis elegans Proteins
0
Proteome
0
Ribosomal Proteins
0
Transcription Factors
0
Doxycycline
N12000U13O
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
549-563.e7Subventions
Organisme : NIGMS NIH HHS
ID : F32 GM119190
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM121176
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests R.H.H. is an inventor on a patent related to mitochondrial ribosomal proteins as aging regulators. The other authors declare that they have no conflicts of interest.
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