# Generating mtDNA mutant mice to model human mitochondrial diseases

> **NIH NIH R21** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2022 · $237,500

## Abstract

Project Summary
Mutations in human mitochondrial DNA (mtDNA) cause maternally inherited diseases that affect
multiple parts of the body including the muscles and nervous system. More than 250 pathogenic
mutations have been identified in human mtDNA, causing a spectrum of pathologies in at least 1
in every 5000 subjects. However, it remains unclear how mtDNA mutations lead to disparate
clinical phenotypes. As there are currently no cures for mitochondrial diseases, in vivo mouse
models harboring pathogenic mtDNA mutations are of critical importance both to understand
disease mechanisms and to develop therapeutic approaches. The lack of such models has
become a major hurdle to research on mitochondrial medicine. The primary challenge to
generate these models originates from the inability to manipulate the mitochondrial genome.
Therefore, this project proposes to build a pipeline to identify specific mouse mtDNA mutations
homologous to disease-causing human mtDNA mutations, select and characterize mouse cells
harboring these mutations, and generate and validate corresponding mutant mouse models.
The key components of our pipeline include a large library of mtDNA mutant mouse cells
containing theoretically all possible mtDNA mutations, a high-throughput high-sensitivity mtDNA
mutation detection assay that can screen tens of thousands of samples per day, and a mouse
embryonic stem cell line that allows quick generation of transmitochondrial mouse lines.
Using this pipeline, the project will generate: 1) mtDNA mutant mouse fibroblast and
embryonic stem cell lines containing mutations homologous to human pathogenic mutations,
and 2) mtDNA mutant mouse models containing such mutations. These in vitro and in vivo tools
would be highly useful in studying the molecular mechanisms of mitochondrial diseases and the
roles of mtDNA mutations in other diseases that are linked with somatic mtDNA mutation
accumulation. The production of these novel tools will also be crucial for therapeutic
development of mitochondrial diseases.

## Key facts

- **NIH application ID:** 10305690
- **Project number:** 5R21OD030076-02
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** Weiwei Fan
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $237,500
- **Award type:** 5
- **Project period:** 2020-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10305690

## Citation

> US National Institutes of Health, RePORTER application 10305690, Generating mtDNA mutant mice to model human mitochondrial diseases (5R21OD030076-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10305690. Licensed CC0.

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