# Pathogenesis of Mitochondrial Retina Disease

> **NIH NIH F30** · UNIVERSITY OF IOWA · 2022 · $37,341

## Abstract

PROJECT SUMMARY
The mitochondrial m.3243A>G variant is a common cause of genetic mitochondrial disease that causes
dysfunction of the retina and other tissues. Due to the high copy number of the mitochondrial genome per cell,
this variant exists in cells across a broad range of proportions. How the proportion of mutant to wildtype
m.3243 allele in any given cell, tissue, or individual relates to the cellular and clinical phenotype is not well
understood. In the proposed research program, we will identify how this variant causes metabolic dysfunction
in ocular cells and in which cell types the variant is preferentially distributed in the retina and underlying
metabolic support tissue during development.
Clinical observation has implicated the retinal pigment epithelium (RPE) as the driver of retinal dystrophy in
m.3243A>G disease. Using induced pluripotent stem cells (iPSCs) derived from patients carrying m.3243A>G,
we will generate RPE containing various controlled proportions of the variant. We will then subject these cells
to a high throughput assay to determine derangement of the normal metabolic program of RPE. This approach
will allow us to determine how increasing levels of m.3243A>G proportion in RPE impacts mitochondrial and
metabolic function.
We and others have previously observed that the m.3243A>G variant segregates non-randomly during the
development of the retina, choroid, and other tissues. Specifically, we have observed in primary ocular tissue
that the choroidal endothelial cells (CEC) that supply nutrients to the RPE and outer retina select against
m.3243A>G. In the proposed research program, we will generate neural retina and CECs from patient iPSCs
and measure the proportion of m.3243A>G to determine if and how these cells are able to select against the
pathogenic variant during in vitro development.
When successful, these studies will advance knowledge of the pathogenicity of the m.3243A>G variant in the
retina. Further understanding the cell type-specific segregation of this mitochondrial variant and the specific
metabolic dysfunctions it causes may lead to novel therapeutic targets for the treatment of this and other retinal
diseases caused by mutations in mitochondrial genes.

## Key facts

- **NIH application ID:** 10463361
- **Project number:** 1F30EY034009-01
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Nathaniel Kevin Mullin
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $37,341
- **Award type:** 1
- **Project period:** 2022-08-10 → 2024-08-09

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463361

## Citation

> US National Institutes of Health, RePORTER application 10463361, Pathogenesis of Mitochondrial Retina Disease (1F30EY034009-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10463361. Licensed CC0.

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