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 regulate nuclear-encoded mitochondrial mRNAs (NEMmRNAs). Our systematic analysis of RNA-targets of 150 RBPs identified RBPs with a preference for binding NEMmRNAs, including LARP4, a La RBP family member. We show that LARP4’s targets are particularly enriched in mRNAs that encode respiratory chain complex proteins (RCCPs) and mitochondrial ribosome proteins (MRPs) across multiple human cell lines. Quantitative proteomics of cells lacking LARP4 show that protein levels of RCCPs and MRPs are significantly reduced. Furthermore, we show that LARP4 depletion reduces mitochondrial function, and that this phenotype is rescued 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. Highlights Analysis of CLIP data reveals RBPs with a preference for mitochondrial mRNA targets LARP4’s RNA-target set is enriched for OXPHOS and mitochondrial ribosomal proteins Loss of LARP4 reduces protein levels of these two groups of mitochondrial proteins LARP4 is required for normal proliferation, translation, and OXPHOS function