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Updated: Apr 8, 2026
Simultaneous Mapping and Quantitation of Ribonucleotides in Human Mitochondrial DNA
Published on: November 14, 2017
Simultaneous DNA and RNA Mapping of Somatic Mitochondrial Mutations across Diverse Human Cancers
James B Stewart1, Babak Alaei-Mahabadi2, Radhakrishnan Sabarinathan3
1Max Planck Institute for Biology of Ageing, Cologne, Germany.
Abstract:
Somatic mutations in the nuclear genome are required for tumor formation, but the functional consequences of somatic mitochondrial DNA (mtDNA) mutations are less understood. Here we identify somatic mtDNA mutations across 527 tumors and 14 cancer types, using an approach that takes advantage of evidence from both genomic and transcriptomic sequencing. We find that there is selective pressure against deleterious coding mutations, supporting that functional mitochondria are required in tumor cells, and also observe a strong mutational strand bias, compatible with endogenous replication-coupled errors as the major source of mutations. Interestingly, while allelic ratios in general were consistent in RNA compared to DNA, some mutations in tRNAs displayed strong allelic imbalances caused by accumulation of unprocessed tRNA precursors. The effect was explained by altered secondary structure, demonstrating that correct tRNA folding is a major determinant for processing of polycistronic mitochondrial transcripts. Additionally, the data suggest that tRNA clusters are preferably processed in the 3' to 5' direction. Our study gives insights into mtDNA function in cancer and answers questions regarding mitochondrial tRNA biogenesis that are difficult to address in controlled experimental systems.
Insights
Somatic mitochondrial DNA (mtDNA) mutations are present in tumors, but their role is unclear. This study reveals selective pressure against harmful mutations and identifies novel insights into mitochondrial tRNA processing and biogenesis in cancer.
Area of Science:
- Genetics
- Cancer Biology
- Mitochondrial Biology
Background:
- Somatic mutations in nuclear DNA are crucial for tumor development.
- The functional impact of somatic mitochondrial DNA (mtDNA) mutations in cancer remains poorly understood.
Purpose of the Study:
- To identify and characterize somatic mtDNA mutations across diverse cancer types.
- To investigate the functional consequences of these mutations on mitochondrial function and tRNA biogenesis in tumor cells.
Main Methods:
- Analysis of genomic and transcriptomic sequencing data from 527 tumors across 14 cancer types.
- Assessment of selective pressures on coding mutations and mutational strand bias.
- Investigation of allelic ratios and tRNA precursor accumulation in relation to mtDNA mutations.
Main Results:
- Evidence of selective pressure against deleterious coding mtDNA mutations, indicating functional mitochondria are necessary for tumor cells.
- A strong mutational strand bias suggests replication-coupled errors as the primary source of mtDNA mutations.
- Identified altered secondary structures in tRNAs leading to unprocessed precursors and allelic imbalances, impacting mitochondrial transcript processing.
Conclusions:
- Functional mitochondria are essential for tumor cell viability, as evidenced by selection against detrimental mtDNA mutations.
- Replication-coupled errors are a major driver of somatic mtDNA mutations.
- Mitochondrial tRNA folding and processing pathways are critical for mitochondrial gene expression and are affected by somatic mutations in cancer.
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