HuR-driven reversible mitochondrial shuttling buffers cytosolic miRNA levels in hepatic cells

Subcellular compartmentalization may be an effective way of controlling the abundance and activity of miRNAs in mammalian cells. Exploring the regulatory processes that control miRNA activity, we found that specific miRNAs are reversibly localized to the mitochondrial matrix in a context-dependent manner. Our data suggest a de novo role of mitochondria as miRNA storage sites in mammalian cells. miR-122 is a key hepatic miRNA regulating metabolic processes in the mammalian liver. In this study, we observed increased mitochondrial targeting of miR-122 in amino acid-starved hepatic cells. Interestingly, when cells are refed with amino acids, mitochondrial miR-122 is relocalized to the cytosol and reused for translational repression. Moreover, this phenomenon is not limited to miR-122, as other mitochondrial-localized miRNAs (mito-miRs) follow similar transient storage inside mitochondria in stressed cells. Bioinformatic analysis revealed that mitochondria-localized mito-miRs preferentially target mRNAs encoding crucial mitochondrial components related to apoptosis. Hence, hepatic cells regulate apoptosis pathways during the starvation-refeeding cycle by shuttling a specific set of miRNAs to and from mitochondria, thereby balancing cytosolic miRNA content. Stress response miRNA binder ELAVL1 or HuR (human antigen R) protein was found to be both necessary and sufficient for transporting the mito-miRs to the mitochondrial matrix-a process also controlled by the interaction between mitochondria and the endoplasmic reticulum.