# Regulation of mitochondrial heteroplasmy dynamics

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2021 · $302,133

## Abstract

PROJECT SUMMARY/ABSTRACT
Mitochondrial dysfunction is a major cellular hallmark of many inherited diseases, as well as age-dependent
degenerative disorders. Mutations in the mitochondrial genome (mtDNA), which encodes essential
components of the electron transport chain, are a common cause of mitochondrial diseases. Mutant mtDNA
copies are frequently co-inherited with wildtype mtDNA in a state of heteroplasmy, and become pathogenic
when their levels reach a critical threshold. Consequently, a central challenge is to understand the processes
that regulate transmission of heteroplasmic mutations through the female germline, and their accumulation in
somatic tissues during aging. Traditionally, studies of mtDNA heteroplasmy dynamics have been hampered by
the need to track heteroplasmy levels across multiple generations, and to do so in a quantitatively rigorous
manner. We have adapted key technological innovations, and have developed Caenorhabditis species of
nematodes as genetically tractable metazoan model systems, to overcome these limitations. We are now
poised to shed light on mechanisms that regulate heteroplasmy dynamics. In aim 1, we will determine the
molecular basis of mtDNA copy number control, which we have discovered is an important determinant of
inherited mutant mtDNA levels. We will do so by using a large collection of heteroplasmic strains that we have
identified from a whole genome sequencing project in C. elegans. In aim 2, we will test the hypothesis that by
allowing cells to tolerate mitochondrial dysfunction, homeostatic stress responses inadvertently allow mutant
mtDNA to rise to pathogenically high levels. We will do so by determining the mechanisms that function
downstream of the mitochondrial unfolded protein response, which we recently reported protects mutant
mtDNA from mitophagy. In aim 3, we will generate heteroplasmies consisting of wildtype mtDNA haplotypes
from two different species of nematodes. We will cross these into different nuclear backgrounds and assess if
there is biased mtDNA transmission to determine the role of the nuclear genome in regulating heteroplasmy
dynamics. Taken together, this research proposal will shed fundamental light on the cellular and molecular
mechanisms that regulate heteroplasmy dynamics. A better understanding of these mechanisms will make it
possible to predict and potentially develop therapeutics to prevent transmission of pathogenic mtDNA
mutations.

## Key facts

- **NIH application ID:** 10137261
- **Project number:** 5R01GM123260-05
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** MAULIK R PATEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $302,133
- **Award type:** 5
- **Project period:** 2017-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10137261

## Citation

> US National Institutes of Health, RePORTER application 10137261, Regulation of mitochondrial heteroplasmy dynamics (5R01GM123260-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10137261. Licensed CC0.

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