Dumas Leïla, Shin Sauyeun, Rigaud Quentin, Cargnello Marie, Hernández-Suárez Beatriz, Herviou Pauline, Saint-Laurent Nathalie, Leduc Marjorie, Le Gall Morgane, Monchaud David, Dassi Erik, Cammas Anne, Millevoi Stefania
Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse, Equipe Labellisée Fondation ARC, Université de Toulouse, Inserm, CNRS, Université Toulouse III-Paul Sabatier, Toulouse, France.
Proteom'IC facility, Université Paris Cité, CNRS, INSERM Institut Cochin, Paris, France.
Nat Commun. 2025 Apr 7;16(1):3292. doi: 10.1038/s41467-025-58118-5.
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.
癌细胞依赖线粒体来提供生物能量和进行大分子合成。线粒体功能的核心是线粒体蛋白质合成的调控，这主要依赖于核编码线粒体mRNA的细胞质翻译，其蛋白质产物会被导入线粒体。尽管越来越多的证据表明线粒体蛋白质合成与癌症的发生和发展有关，从而可能为癌症治疗提供新的机会，但对其潜在分子机制的了解仍然有限。在这里，我们表明RNA G-四链体（RG4s）通过调节核编码线粒体蛋白的细胞质mRNA翻译来调控线粒体功能。我们的数据支持一种模型，即RG4折叠动力学在致癌信号的控制下，受到小分子配体或RG4结合蛋白的调节，从而改变线粒体定位的细胞质蛋白质合成。最终，这会损害线粒体功能，影响能量代谢，进而影响癌细胞增殖。
