A Conserved Mito-Cytosolic Translational Balance Links Two Longevity Pathways

• Published in: Cell metabolism Vol. 31; no. 3; pp. 549 - 563.e7
• Main Authors: Molenaars, Marte, Janssens, Georges E., Williams, Evan G., Jongejan, Aldo, Lan, Jiayi, Rabot, Sylvie, Joly, Fatima, Moerland, Perry D., Schomakers, Bauke V., Lezzerini, Marco, Liu, Yasmine J., McCormick, Mark A., Kennedy, Brian K., van Weeghel, Michel, van Kampen, Antoine H.C., Aebersold, Ruedi, MacInnes, Alyson W., Houtkooper, Riekelt H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.03.2020; Elsevier
• Subjects: aging; ATF4; cytosolic translation; doxycycline; Life Sciences; longevity; mitochondrial translation; polysome; ribosomes; translational balance; translational efficiency; mitochondrial translation; ribosomes; cytosolic translation; polysome; longevity; translational balance; aging; doxycycline; translational efficiency; ATF4
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2020.01.011

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. [Display omitted] •Mitochondrial and cytosolic ribosomal proteins are balanced with a natural ratio•Blocking mitochondrial ribosomes in worms and mice reduces cytosolic translation•Translational balance is ATF4/atf-5-dependent and conserved in human cells•atf-5-induced translational repression is independent from mitochondrial bioenergetics Molenaars, Janssens, and colleagues report on a natural balance between cytosolic and mitochondrial ribosomal proteins, driven by an active link between two longevity pathways. They demonstrate that the inhibition of mitochondrial translation regulates cytosolic translation via the transcription factor Atf4/atf-5, a phenomenon conserved in worms, human cells, and in vivo in mice.