A conserved mito-cytoplasmic translational balance links two longevity pathways
Marte Molenaars*, Georges E. Janssens*, Jiayi Lan, Aldo Jongejan, Perry Moerland, Antoine van Kampen, Evan G. Williams, Ruedi Aebersold, Alyson W. MacInnes, Riekelt Houtkooper. * equal contribution.
Slowing down mRNA translation and protein synthesis in either the cytosol or the mitochondria are both conserved longevity mechanisms. Here, we found a non-interventional natural correlation of mitochondrial and cytosolic ribosomal proteins when looking at mouse population genetics, suggesting a mito-cytosolic translational balance. In addition, inhibition of mitochondrial translation in C. elegans using RNAi of mitochondrial ribosomal protein S5 (mrps-5) reduced the translational efficiency (TE) of mRNAs coding for cytosolic ribosomal proteins. This in turn repressed cytosolic translation and growth pathways while upregulating stress responses at both the proteome and transcriptome levels. We found that this coordinated repression of cytosolic translation is dependent on the atf-5/Atf4 transcription factor. This coordination is conserved in mammalian cells treated with the antibiotic doxycycline to reduce mitochondrial translation, suggesting the potential for further pharmacological development. Lastly, this coordination is also conserved in vivo in mice treated with doxycycline, with cross-species transcriptomics revealing a conserved mito-cytosolic translational balance. Together these data demonstrate that inhibiting mitochondrial translation initiates a signaling cascade leading to a coordinated repression of cytosolic translation, which goes against the previously described unidirectional mito-cytosolictranslational communication in yeast. We propose that this bi-directional translational balance has strong potential to be targeted to promote healthy aging.
No financial interests to disclose
Slowing down mRNA translation and protein synthesis in either the cytosol or the mitochondria are both conserved longevity mechanisms. Here, we found a non-interventional natural correlation of mitochondrial and cytosolic ribosomal proteins when looking at mouse population genetics, suggesting a mito-cytosolic translational balance. In addition, inhibition of mitochondrial translation in C. elegans using RNAi of mitochondrial ribosomal protein S5 (mrps-5) reduced the translational efficiency (TE) of mRNAs coding for cytosolic ribosomal proteins. This in turn repressed cytosolic translation and growth pathways while upregulating stress responses at both the proteome and transcriptome levels. We found that this coordinated repression of cytosolic translation is dependent on the atf-5/Atf4 transcription factor. This coordination is conserved in mammalian cells treated with the antibiotic doxycycline to reduce mitochondrial translation, suggesting the potential for further pharmacological development. Lastly, this coordination is also conserved in vivo in mice treated with doxycycline, with cross-species transcriptomics revealing a conserved mito-cytosolic translational balance. Together these data demonstrate that inhibiting mitochondrial translation initiates a signaling cascade leading to a coordinated repression of cytosolic translation, which goes against the previously described unidirectional mito-cytosolictranslational communication in yeast. We propose that this bi-directional translational balance has strong potential to be targeted to promote healthy aging.
No financial interests to disclose
