Functionally dominant hotspot mutations of mitochondrial ribosomal RNA genes in cancer - Nature Genetics

Functionally dominant hotspot mutations of mitochondrial ribosomal RNA genes in cancer

Analysis of 14,106 tumor genomes revealed recurrent mutations in mitochondrial ribosomal RNA encoded within the mitochondrial genome. These mutations appear at specific hotspot positions and are strongly conserved in the germline, suggesting purifying selection.

While most common somatic mutations in tumors affect nuclear protein-coding genes, this large-scale study identified frequent mutations in both the small (12S, MT-RNR1) and large (16S, MT-RNR2) mitochondrial RNA subunits of the mitoribosome. These hotspots are typically located in positions conserved by selection and form structural clusters at regions interacting with mRNA and tRNA within the mitochondrial ribosome.

Researchers used precision mitochondrial DNA base editing to model an exemplary MT-RNR1 hotspot mutation, m.1227G>A. Multimodal profiling showed that this variant causes a heteroplasmy-dependent decline in mitochondrial performance, along with a loss of respiratory chain subunits once mutant load reaches about 10%.

Mutation of conserved positions in ribosomal RNA that disrupt mitochondrial translation represent a class of functionally dominant, pathogenic mtDNA mutations under positive selection in cancer genomes.

Author’s Summary

Recurrent mitochondrial rRNA mutations form a distinct, positively selected group in cancers, linking ribosomal RNA alteration to impaired respiration and tumor progression.

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Nature Nature — 2025-11-04

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