RNA G-quadruplexes control mitochondria-localized mRNA translation and energy metabolism
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.
Authors
- Marie Cargnello (ORCID: https://orcid.org/0000-0002-1060-0478)
- Pauline Herviou (ORCID: https://orcid.org/0009-0008-1927-1843)
- Beatriz Hernández‐Suárez (ORCID: https://orcid.org/0000-0002-5377-6609)
- Stefania Millevoi (ORCID: https://orcid.org/0000-0003-1659-3552)
- David Monchaud (ORCID: https://orcid.org/0000-0002-3056-9295)
- Morgane Le Gall (ORCID: https://orcid.org/0000-0002-4935-7065)
- Sauyeun Shin
- Nathalie Saint‐Laurent
- Erik Dassi (ORCID: https://orcid.org/0000-0003-4487-0449)
- Anne Cammas (ORCID: https://orcid.org/0000-0002-3240-9172)
- Marjorie Leduc (ORCID: https://orcid.org/0000-0002-4049-3976)
- Quentin Rigaud
- Leïla Dumas
Institutions
- Centre National de la Recherche Scientifique (FR)
- Université Toulouse III - Paul Sabatier (FR)
- Inserm (FR)
- University of Trento (IT)
- Université Paris Cité (FR)
- Centre de Recherches en Cancérologie de Toulouse (FR)
- Laboratoire de Chimie Moléculaire (FR)
- Institut Cochin (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-07
- DOI
- https://doi.org/10.1038/s41467-025-58118-5
- Citations
- 11
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 8.06
Funders
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Ligue Contre le Cancer
- Université de Toulouse
- Centre National de la Recherche Scientifique
- Université Claude Bernard Lyon 1
- Université de Paris