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 also participate in metabolic reprogramming, oxidative stress, apoptosis regulation and other key processes. For a long time, mitochondrial dysfunction has been regarded as closely linked to cancer: tumor cells often show the so-called “Warburg effect” in mitochondrial metabolism (a reliance on glycolysis for energy), yet some tumors remain dependent on intact mitochondrial function to sustain proliferation.
Mitochondrial ribosomes are responsible for synthesizing the mitochondrially encoded subunits of the OXPHOS complexes, and mt-rRNA is the core component of the mitochondrial ribosome. Previous work has already shown that mitochondrial DNA (mtDNA) mutations are present in cancers, but the mutation patterns, functional impact and clinical significance of mt-rRNA genes themselves have not been systematically analyzed. This gap becomes the main entry point of the present study, from the mitochondrial ribosome side.
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. Unlike random mutations, these hotspots show clear functional dominance, mainly in the following aspects:
1. Selectivity and conservation of the mutations
The hotspot sites are highly conserved and cluster within functional domains of mt-rRNA, such as the contact regions between small and large ribosomal subunits and tRNA-binding sites. This strong conservation suggests that these changes are not just simple random events, but mutations that can alter the structure and function of the mitochondrial ribosome and thereby confer a survival advantage on tumor cells.
2. Regulation of mitochondrial translation and metabolism
Functional experiments show that mt-rRNA carrying hotspot mutations leads to abnormal translational efficiency of the mitochondrial ribosome. Some mutations enhance synthesis of OXPHOS complex subunits and drive a mitochondrial-dependent metabolic state in tumor cells. Other mutations interfere with translational fidelity, causing misfolding of mitochondrial proteins and activating the mitochondrial unfolded protein response (mt-UPR), which reshapes tumor cell metabolism and stress adaptation capacity.
3. Coordination with the tumor microenvironment and proliferation
In vivo and in vitro experiments indicate that mt-rRNA hotspot mutations promote tumor cell proliferation, invasion and drug resistance. Mechanistically, this is linked to cross-talk between metabolism and signaling: mitochondrial metabolic reprogramming triggered by the mutations activates downstream oncogenic pathways (such as PI3K–AKT and MAPK), while at the same time altering nutrient competition and immune-escape features within the tumor microenvironment.
Starting from the relatively “niche” perspective of the mitochondrial ribosome, this work opens up a new dimension for understanding cancer development. It provides key clues to how tumor metabolic reprogramming is coupled to molecular regulatory networks and also brings fresh ideas for more personalized cancer therapy.
Original article: https://www.nature.com/articles/s41588-025-02374-0
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