Localization of RNAs to the mitochondria-mechanisms and functions

The mammalian mitochondrial proteome comprises over 1000 proteins, with the majority translated from nuclear-encoded messenger RNAs (mRNAs). Mounting evidence suggests many of these mRNAs are localized to the outer mitochondrial membrane (OMM) in a pre- or cotranslational state. Upon reaching the mitochondrial surface, these mRNAs are locally translated to produce proteins that are cotranslationally imported into mitochondria. Here, we summarize various mechanisms cells use to localize RNAs, including transfer RNAs (tRNAs), to the OMM and recent technological advancements in the field to study these processes. While most early studies in the field were carried out in yeast, recent studies reveal RNA localization to the OMM and their regulation in higher organisms. Various factors regulate this localization process, including RNA sequence elements, RNA-binding proteins (RBPs), cytoskeletal motors, and translation machinery. In this review, we also highlight the role of RNA structures and modifications in mitochondrial RNA localization and discuss how these features can alter the binding properties of RNAs. Finally, in addition to RNAs related to mitochondrial function, RNAs involved in other cellular processes can also localize to the OMM, including those implicated in the innate immune response and piRNA biogenesis. As impairment of messenger RNA (mRNA) localization and regulation compromise mitochondrial function, future studies will undoubtedly expand our understanding of how RNAs localize to the OMM and investigate the consequences of their mislocalization in disorders, particularly neurodegenerative diseases, muscular dystrophies, and cancers.