Hallmarks of slow translation initiation revealed in mitochondrially localizing mRNA sequences

ABSTRACT The mRNA of some, but not all, nuclear encoded mitochondrial proteins localize to the periphery of mitochondria. Previous studies have shown that both the nascent polypeptide chain and an mRNA binding protein play a role in this phenomenon, and have noted a positive correlation between mRNA length and mitochondrial localization. Here, we report the first investigation into the relationship between mRNA translation initiation rate and mRNA mitochondrial localization. Our results indicate that translation initiation promoting factors such as Kozak sequences are associated with cytosolic localization, while inhibiting factors such as 5′ UTR secondary structure correlate with mitochondrial localization. Moreover, the frequencies of nucleotides in various positions of the 5′ UTR show higher correlation with localization than the 3′ UTR. These results indicate that mitochondrial localization is associated with slow translation initiation. Interestingly this may help explain why short mRNAs, which are thought to initiate translation rapidly, seldom localize to mitochondria. We propose a model in which translating mRNA has reduced mobility and tends not to reach mitochondria. Finally, we explore this model with a simulation of mRNA diffusion using previously estimated translation initiation probabilities, confirming that our model can produce localization values similar to those measured in experimental studies.