Gombeau, K.; Wan, R.; James, J. S.; Tribouillard-Tanvier, D.; Cai, Y.

Mitochondria are essential organelles containing their own genomes, encoding a few proteins essential for energy production. Most of themitochondrial proteins are nucleus-encoded, translated as precursors in the cytoplasm, with a large fraction of these precursors properly addressedby an N-terminal mitochondrial targeting sequence (MTS). These MTS share common features but no consensus sequence can explain theirfunctionality nor the precursors-specific determinants of mitochondrial import. To decipher this mechanism, we created a simple computationalmodel to generate highly functional synthetic MTS while maintaining a tight control on the design parameters. Using the budding yeast, wedemonstrated the presence of precursors-specific signatures in addressing artificially nucleus-relocated OXPHOS proteins. We also show theability of six promising candidate synthetic MTS to address a fluorescent reporter to human mitochondria cells. Our research work confirms theuniqueness of the MTS-passenger protein synergy and takes us one step closer towards improving gene therapy-based treatment of mitochondrialdiseases