# Mechanisms of mitochondrial DNA copy number regulation

> **NIH NIH F31** · VANDERBILT UNIVERSITY · 2021 · $8,790

## Abstract

PROJECT SUMMARY
Mitochondrial dysfunction underlies many metabolic conditions and results in poor health outcomes.
Mitochondrial DNA (mtDNA) reside in the mitochondria and encode essential components of the electron
transport chain. The electron transport chain generates ATP via oxidative phosphorylation: a key role that
mitochondria play in energy production and metabolism. mtDNA can exist in hundreds to thousands of copies
per cell and, unlike the nuclear genome, mtDNA copy number per cell can be modulated in response to energy
demand, resulting in variable mtDNA copy number. Importantly, proper mtDNA copy number is crucial for survival
as insufficient mtDNA copy number can result in mtDNA depletion syndromes leading to myopathies. Taken
together, the variability of mtDNA copy number coupled with the consequences of low copy number suggest a
mechanism of tightly controlled mtDNA copy number regulation. Though mtDNA replication has been extensively
studied, the mechanism of copy number control remains poorly understood due to a lack of appropriate tools. I
have adapted Caenorhabditis elegans as a model to study mtDNA copy number regulation in metazoans. Using
quantitative techniques I have developed to measure mtDNA copy number in single worms, I have discovered
active regulation of mtDNA copy number in the C. elegans germline. Additionally, my preliminary data suggest
that an output generated by the electron transport chain is used by the cell to “count” mtDNA copies. My data
and innovations uniquely position me to identify the mechanisms of copy number regulation in the C. elegans
germline. In aim 1 I propose to identify the electron transport chain components necessary for mtDNA copies to
be counted, using a large collection of heteroplasmic strains. Heteroplasmies contain mtDNA with two distinct
haplotypes and offer means to identify the minimal requirements for mitochondrial genome counting. In aim 2 I
propose to identify the sensor that acts to regulate copy number using a targeted RNAi screen. In aim 3 I propose
to determine whether mtDNA copy number is regulated at the genome or organelle level using high resolution
microscopy. Taken together, these experiments will identify mechanisms of mtDNA copy number regulation.
Understanding mtDNA copy number regulation will pave the way for therapeutic options for individuals with
mtDNA depletion syndromes.

## Key facts

- **NIH application ID:** 10062510
- **Project number:** 5F31GM131581-03
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Caitlyn Kirby
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $8,790
- **Award type:** 5
- **Project period:** 2018-12-01 → 2021-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10062510

## Citation

> US National Institutes of Health, RePORTER application 10062510, Mechanisms of mitochondrial DNA copy number regulation (5F31GM131581-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10062510. Licensed CC0.

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