TargetMITO: a rule-based model for generating functional synthetic mitochondrial targeting sequences in yeast

Mitochondria are essential organelles containing their own genomes, encoding a few proteins essential for energy production. Most of the mitochondrial proteins are nucleus-encoded, translated as precursors in the cytosol, with a large fraction of these precursors properly addressed by an N-terminal mitochondrial targeting sequence (MTS). These MTS share common features but no consensus sequence can explain their functionality nor the precursors-specific determinants of mitochondrial import. To help understand this mechanism, we created a simple computational model to generate functional synthetic MTS while maintaining a tight control on the design parameters. Using the budding yeast, we demonstrated the presence of precursors-specific import capabilities in addressing artificially nucleus-relocated OXPHOS proteins. Our research confirms the existence of cargo-dependent functional compatibilities and takes us one step closer towards improving gene therapy-based treatment of mitochondrial diseases.