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Author Spotlight: High-Throughput Image-Based Quantification of Mitochondrial DNA Synthesis and Distribution
Published on: May 5, 2023
Mitochondrial DNA exhibits resistance to induced point and deletion mutations
William J Valente1, Nolan G Ericson2, Alexandra S Long3
1Translational Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA Medical Scientist Training Program, University of Washington School of Medicine, Seattle, WA 98195, USA Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA 98195, USA.
Abstract:
The accumulation of somatic mitochondrial DNA (mtDNA) mutations contributes to the pathogenesis of human disease. Currently, mitochondrial mutations are largely considered results of inaccurate processing of its heavily damaged genome. However, mainly from a lack of methods to monitor mtDNA mutations with sufficient sensitivity and accuracy, a link between mtDNA damage and mutation has not been established. To test the hypothesis that mtDNA-damaging agents induce mtDNA mutations, we exposed MutaTMMouse mice to benzo[a]pyrene (B[a]P) or N-ethyl-N-nitrosourea (ENU), daily for 28 consecutive days, and quantified mtDNA point and deletion mutations in bone marrow and liver using our newly developed Digital Random Mutation Capture (dRMC) and Digital Deletion Detection (3D) assays. Surprisingly, our results demonstrate mutagen treatment did not increase mitochondrial point or deletion mutation frequencies, despite evidence both compounds increase nuclear DNA mutations and demonstrated B[a]P adduct formation in mtDNA. These findings contradict models of mtDNA mutagenesis that assert the elevated rate of mtDNA mutation stems from damage sensitivity and abridged repair capacity. Rather, our results demonstrate induced mtDNA damage does not readily convert into mutation. These findings suggest robust mitochondrial damage responses repress induced mutations after mutagen exposure.
Insights
Mitochondrial DNA (mtDNA) damage does not directly cause mutations. Robust cellular responses appear to prevent induced mtDNA damage from converting into mutations, challenging current mutagenesis models.
Area of Science:
- Mitochondrial biology
- Toxicology
- Genetics
Background:
- Somatic mitochondrial DNA (mtDNA) mutations are implicated in human diseases.
- Current models suggest mtDNA mutations arise from processing its damaged genome.
- A direct link between mtDNA damage and mutation has been difficult to establish due to methodological limitations.
Purpose of the Study:
- To investigate whether exposure to mutagenic agents induces mtDNA point and deletion mutations.
- To test the hypothesis that mtDNA-damaging agents increase mtDNA mutation frequency.
Main Methods:
- Mice were exposed to benzo[a]pyrene (B[a]P) or N-ethyl-N-nitrosourea (ENU) for 28 days.
- Quantification of mtDNA point and deletion mutations using Digital Random Mutation Capture (dRMC) and Digital Deletion Detection (3D) assays.
- Assessment of B[a]P adduct formation in mtDNA.
Main Results:
- Mutagen treatment did not increase mtDNA point or deletion mutation frequencies in bone marrow or liver.
- Evidence confirmed B[a]P formed adducts in mtDNA and both mutagens increased nuclear DNA mutations.
- Induced mtDNA damage did not readily convert into mutations.
Conclusions:
- Findings contradict models positing that mtDNA mutation rates stem from damage sensitivity and poor repair.
- Robust mitochondrial damage response mechanisms appear to repress induced mutations following mutagen exposure.
- Induced mtDNA damage does not directly lead to mutation accumulation.
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