Mitochondrial volume fraction controls translation of nuclear-encoded mitochondrial proteins

Abstract

Mitochondria are dynamic in their size and morphology yet must also precisely control their protein composition according to cellular energy demand. Although nuclear-encoded mRNAs can be localized to the mitochondrial outer membrane, the importance of this localization in altering mitochondrial protein composition is unclear. We have found that, as yeast switch from fermentative to respiratory metabolism, there is an increase in the fraction of the cytoplasm that is mitochondrial. This drives the localization of certain nuclear-encoded mitochondrial mRNAs to the surface of the mitochondria. Through tethering experiments, we show that mitochondrial mRNA localization is necessary and sufficient to increase protein production to levels required during respiratory growth. Furthermore, we find that ribosome stalling impacts mRNA sensitivity to mitochondrial volume fraction and counterintuitively leads to enhanced protein synthesis by increasing mRNA localization to the mitochondria. This points to a mechanism by which cells are able to use translation elongation and the geometric constraints of the cell to fine-tune organelle-specific gene expression through mRNA localization while potentially circumventing the need to directly coordinate with the nuclear genome. mitochondria | geometric constraints | mRNA localization | translation control

Co-translational targeting of transcripts to endosomes

“…While still relying on ribosome association, these mechanisms do not depend on some property in the nascent protein. Such ribosome association-dependent localization of transcripts has also been described for organelles other than the ER, such as mitochondria 5,6,7 . To identify mRNA-associated factors that might be involved in the case of EEA1 transcript targeting to endosomes, we developed an assay for the specific isolation of endogenous EEA1 transcripts together with its associated proteome.…”

Start codon context controls translation initiation in the fungal kingdom

“…Mechanisms to control initiation efficiency of a mitochondrial-localized regulon could include intracellular magnesium concentration (73), variations in availability or modification status of shared initiation factors, variations of the ratio of mitochondrial volume to intracellular volume (74), or specialized factors to promote initiation specifically of mitochondrial isoforms with their specialized start codon context. Nakagawa et al (75) previously suggested that distinct Kozak contexts might be recognized by different molecular mechanisms.…”

Cytosolic Events in the Biogenesis of Mitochondrial Proteins

“…Indeed, localization of many mRNAs to mitochondria was shown to depend on their translation and the presence of the Tom20 receptor that binds MTSs [22,44]. If a transcript is very long or translation is slowed down by rare codons, RNCs that already synthetized an MTS may have time to associate with mitochondria [45]. However, it was proposed that some additional factors may specifically recruit RNCs to the mitochondrial OMs and act via binding the ribosome itself [46,47].…”