LARP4 Is an RNA-Binding Protein That Binds Nuclear-Encoded Mitochondrial mRNAs To Promote Mitochondrial Function

Mitochondrial associated RNA-binding proteins (RBPs) have emerged as key contributors to mitochondrial biogenesis and homeostasis. With few examples described, we set out to identify RBPs that post-transcriptionally regulate nuclear-encoded mitochondrial mRNAs (NEMmRNAs). Our analysis of RNA-target sets of RBPs made available by ENCODE identified several RBPs with a preference for binding NEMmRNAs, of which we selected LARP4, a La RBP family member, for further study. We show that LARP4’s RNA-target set is particularly enriched in mRNAs that encode for respiratory chain complex proteins (RCCPs) and mitochondrial ribosome proteins (MRPs) across multiple human cell lines. CRISPR knockout cells in conjunction with quantitative proteomics show that protein levels of RCCPs and MRPs are significantly reduced upon loss of LARP4. Furthermore, we show that LARP4 depletion reduces mitochondrial function, and this phenotype is ameliorated by LARP4 re-expression. Our findings shed light onto a novel function for LARP4 as an RBP that binds to NEMmRNAs to promote mitochondrial respiratory function. Identification of LARP4 targets using eCLIP-seq in HEK293 cell line