Hitch-hiking of transcripts on organelles, including mitochondria, has emerged as a common pathway to transport mRNAs into the axon to enable their local translation. However, the extent of mitochondr...

Selective ribosome profiling reveals that nearly 20% of mitochondrial proteins in human cells are imported during translation on cytosolic ribosomes. Cotranslational import requires an N-terminal presequence but is delayed until a large domain emerges and prioritizes large multi-domain proteins. This multi-layered sorting mechanism enables cells to balance the import demands for the mitochondrial proteome with diverse biophysical properties.