RNA G-quadruplex dynamics steers the crosstalk between protein synthesis and energy metabolism

Cancer cells rely on mitochondria for their bioenergetic machinery and macromolecule synthesis. The regulation of mitochondrial protein synthesis is central to mitochondrial function. This process primarily depends on the cytoplasmic translation of nuclear-encoded mitochondrial mRNAs whose protein products are imported into mitochondria. Despite the growing evidence that mitochondrial protein synthesis contributes to the onset and progression of cancer, and offers new opportunities for cancer therapy, knowledge of the underlying molecular mechanisms remains limited. Here, we show that RNA G-quadruplexes (RG4s) are localized to mitochondria and regulate mitochondrial function by modulating cytoplasmic mRNA translation of nuclear-encoded mitochondrial proteins . Our data support a model whereby RG4 stabilization induced by small molecule ligands or by depleting RG4-binding proteins alters nuclear-encoded mitochondrial mRNAs protein synthesis. Ultimately, this impairs mitochondrial functions, affecting energy metabolism and consequently cancer cell proliferation. Overall design: Total and polysomal profiling of 3 biological replicates of wild-type and HNRNPU-silenced HCT116 cells