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RNA G-quadruplexes control mitochondria-localized mRNA translation and energy metabolism
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Edité par CCSD ; Nature Publishing Group -
International audience. Cancer cells rely on mitochondria for their bioenergetic supply and macromolecule synthesis. Central to mitochondrial function is the regulation of mitochondrial protein synthesis, which 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 can thus offer new opportunities for cancer therapy, knowledge of the underlying molecular mechanisms remains limited. Here, we show that RNA G-quadruplexes (RG4s) regulate mitochondrial function by modulating cytoplasmic mRNA translation of nuclear-encoded mitochondrial proteins. Our data support a model whereby the RG4 folding dynamics, under the control of oncogenic signaling and modulated by small molecule ligands or RG4-binding proteins, modifies mitochondria-localized cytoplasmic protein synthesis. Ultimately, this impairs mitochondrial functions, affecting energy metabolism and consequently cancer cell proliferation.
Contrary to conventional wisdom 1 , accumulating evidence supports the notion that mitochondrial metabolism is active in cancer cells and required for tumor growth, as it fuels the bioenergetic and biosynthetic needs of cancer cells 2 . Metabolic reprogramming with increased dependence on mitochondrial functions may increase during tumor progression 3 and in response to therapies 4,5 . Central to the mitochondrial function is the regulation of mitochondrial protein synthesis, which relies primarily on the cytoplasmic translation of nuclear-encoded mitochondrial mRNAs whose protein products are then imported into mitochondria 6 . The majority of these proteins are directly or indirectly involved in the mitochondrial translation of 13 mitochondrial-encoded membrane proteins.
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