# Temporal control of mitochondrial mutagenesis

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2023 · $519,553

## Abstract

ABSTRACT
To fully understand the basic biology that underlies human aging, and accurately time potential treatments that
are aimed at preventing age-related pathology, it will be of vital importance to determine when the events that
precipitate human aging occur. One of the processes that drives human aging is mitochondrial mutagenesis.
Mitochondrial DNA (mtDNA) mutations accumulate as we grow older, which accelerates the natural aging
process and contributes to various age-related diseases, including cancer, muscle wasting and
neurodegeneration. However, due to the multiplicity of mitochondrial genomes in a cell, de novo mtDNA
mutations are initially harmless. MtDNA mutations need to clonally expand to cause disease. Because this
expansion process takes time, we hypothesize that the mutations that precipitate age-related pathology arise
relatively early in life, and that the pace of mitochondrial aging is set long before pathology becomes apparent.
We propose to test this hypothesis with a new mouse model of DNA polymerase gamma (PolgA), the enzyme
that replicates the mitochondrial genome. This model expresses an error prone version of DNA polymerase
gamma that can be replaced with a WT allele at will. Accordingly, we can turn off mitochondrial mutagenesis at
any time during the animal’s lifespan and determine how mutations that occur early in life affect pathology later
in life. In addition, we will use various mutation detection techniques, including random mutation capture, single
cell sequencing and duplex sequencing to track the fate of these mutations over the lifespan of our mice.
These experiments will describe the natural history of every possible mtDNA mutation in various tissues,
effectively dissecting the parameters that control the impact of mtDNA mutations on human health. Finally, we
propose to rejuvenate somatic cells and aging mice by manipulating mitochondrial fusion and mitophagy, in an
attempt to cure them from deleterious mtDNA mutations. If successful, this strategy could provide a potential
treatment for multiple pediatric mtDNA diseases, as well as the mitochondrial component of age-related
diseases. Accordingly, our experiments have the potential to revolutionize our understanding of the relationship
between mitochondrial mutagenesis and aging, and provide powerful new tools to combat both inherited and
age-related diseases that are associated with mtDNA mutations.

## Key facts

- **NIH application ID:** 10709005
- **Project number:** 5R01AG075130-02
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Marc Vermulst
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $519,553
- **Award type:** 5
- **Project period:** 2022-09-30 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10709005

## Citation

> US National Institutes of Health, RePORTER application 10709005, Temporal control of mitochondrial mutagenesis (5R01AG075130-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10709005. Licensed CC0.

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