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Published on: September 17, 2020
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A Conserved Mito-Cytosolic Translational Balance Links Two Longevity Pathways.
Marte Molenaars1, Georges E Janssens1, Evan G Williams2
1Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands.
Cell Metabolism
|February 22, 2020
Summary
Slowing protein synthesis in mitochondria or the cytosol promotes longevity. Inhibiting mitochondrial translation triggers a conserved cascade that represses cytosolic translation, offering a new target for longevity research.
Area of Science:
- Cellular Biology
- Genetics
- Aging Research
Background:
- Slowing translation in the cytosol or mitochondria is a known longevity mechanism.
- A natural correlation between mitochondrial and cytosolic ribosomal proteins suggests translational balance.
Purpose of the Study:
- To investigate the relationship between mitochondrial and cytosolic translation.
- To explore the role of translational balance in longevity.
- To identify conserved mechanisms linking mitochondrial function to cytosolic translation.
Main Methods:
- RNA interference (RNAi) in C. elegans to inhibit mitochondrial translation.
- Transcriptomics and proteomics to analyze mRNA and protein changes.
- Pharmacological inhibition of mitochondrial translation with doxycycline in mammalian cells and mice.
- Genetic analysis of ATF4 pathway involvement.
Main Results:
- Mitochondrial translation inhibition in C. elegans repressed cytosolic translation and extended lifespan.
- This repression specifically affected growth and stress response mRNAs.
- The effects were dependent on the ATF4 transcription factor and independent of metabolic changes.
- Translational balance was conserved in mammalian cells and mouse livers.
Conclusions:
- Inhibiting mitochondrial translation initiates an ATF4-dependent cascade that coordinately represses cytosolic translation.
- This coordinated translational repression is a conserved mechanism linked to longevity.
- Targeting this pathway offers a potential strategy for promoting lifespan extension.
Keywords:
ATF4agingcytosolic translationdoxycyclinelongevitymitochondrial translationpolysomeribosomestranslational balancetranslational efficiencyMore Related Videos
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