# Investigating the impact and dynamic of mitochondrial common deletion in somatic cells

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $542,924

## Abstract

Project Summary:
The most common mitochondrial DNA (mtDNA) abnormality is a deletion of 4977 base pairs
called the common deletion (CD), associated with mitochondrial pathologies and widespread in
aging. The CD primarily manifests in the brain and muscles when deleted molecules exceed
60% of total copies, known as heteroplasmy. However, the mechanisms that cause harmful
deletions and why neuronal and muscle cells are particularly vulnerable to CD remain unclear.
Major obstacles to studying the CD is the lack of tools to manipulate mtDNA and the inability to
generate the CD in a controlled manner. Here, we developed a series of methodologies to
overcome these barriers. Specifically, we generated an inducible quasi-dimeric TALEN that
generates the CD in isogenic settings and at defined heteroplasmy states. With this tool, we will
establish low, medium, and high levels of CD heteroplasmy in embryonic stem cells that we will
then differentiate into muscle, neuronal, and fibroblast cells and elucidate the consequence of
this harmful deletion in a cell-type-specific manner and its impact on cellular aging. Furthermore,
we will explore the cell-type-specific distribution of CD, Identifying the pathways that sustain
mutant mtDNA propagation in post-mitotic cells while promoting its elimination in dividing cells.
Combining novel genetic tools with extensive experience in genome stability will resolve the
long-standing mystery of preferential mutant mtDNA propagation in post-mitotic cells and have
significant implications for numerous mitochondrial pathologies and aging.

## Key facts

- **NIH application ID:** 10933021
- **Project number:** 5R01AG085782-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Agnel Sfeir
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $542,924
- **Award type:** 5
- **Project period:** 2023-09-30 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10933021

## Citation

> US National Institutes of Health, RePORTER application 10933021, Investigating the impact and dynamic of mitochondrial common deletion in somatic cells (5R01AG085782-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10933021. Licensed CC0.

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