On 3 November 2025, Nature Genetics published online an open-access research article titled “Functionally dominant hotspot mutations of mitochondrial ribosomal RNA genes in cancer”. The study focuses on hotspot mutations in mitochondrial ribosomal RNA (mt-rRNA) genes in human cancers and reveals their functionally dominant roles in tumor initiation and progression.
Mitochondria generate ATP through oxidative phosphorylation (OXPHOS) and participate in metabolic reprogramming, oxidative stress, and apoptosis regulation. For a long time, mitochondrial dysfunction has been regarded as closely linked to cancer.
Key findings: the “functional dominance” of hotspot mutations
By large-scale analysis of cancer genome datasets, the authors identified high-frequency hotspot mutations in mt-rRNA genes across multiple tumor types, including colorectal, lung and breast cancer.
1. Selectivity and conservation
The hotspot sites are highly conserved and cluster within functional domains of mt-rRNA. This suggests these changes are not random events, but mutations that confer a survival advantage on tumor cells.
2. Regulation of mitochondrial translation
Functional experiments show that mt-rRNA hotspot mutations lead to abnormal translational efficiency, activating the mitochondrial unfolded protein response (mt-UPR).
3. Coordination with the tumor microenvironment
Mutations promote tumor cell proliferation and drug resistance, activating oncogenic pathways such as PI3K–AKT and MAPK.
Original article: https://www.nature.com/articles/s41588-025-02374-0
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