# Mitochondrial Respiratory Chain Dysfunction in Primary Open Angle Glaucoma

> **NIH NIH K08** · UNIVERSITY OF PENNSYLVANIA · 2021 · $227,417

## Abstract

Project Summary/Abstract: A growing body of evidence suggests that secondary mitochondrial dysfunction
underlies numerous complex diseases including glaucoma. Primary open angle glaucoma (POAG) is the most
common form of glaucoma. It represents a group of disorders with population-associated variations in course
and severity, which likely signify differences in pathogenesis, some of which may be associated with
mitochondrial dysfunction. Mitochondrial haplogroups correspond to maternally-determined geographic
populations, and may be protective or confer a higher risk for certain diseases. Utilizing the Primary Open-
Angle African-American Glaucoma Genetics database, the PI found worse glaucomatous cupping and more
severe visual field loss in the L1c2 haplogroup compared to the closely associated L1b haplogroup despite
comparable age, sex, and intraocular pressure (IOP). L1c2 is defined by two missense mutations affecting the
mitochondrial gene cytochrome c oxidase I (COI), which encodes a key component of the mitochondrial
electron transport/respiratory chain (RC) Complex IV. The RC is the site of ATP synthesis and a primary site
for reactive oxygen species generation, disturbances of which have been implicated in glaucoma. In mice with
a COI mutation and reduces Complex IV activity, the PI found decreased number of RGCs in male mutants
compared to controls, suggesting decreased
RC
function
predisposes to optic neuropathies such as ones
resulting from glaucoma. The PI hypothesizes that inherited variations of RC subunits cause impaired
mitochondrial respiration, which confers increased susceptibility to RGC loss and to additional stressors like
elevated IOP, manifesting as glaucomatous optic neuropathy. Specific aims will: 1) Determine the ocular
phenotype and mitochondrial function in a murine model of COI mutation at baseline and in the setting of
induced ocular hypertension; and 2) assess the ocular phenotype and mitochondrial function in POAG patients
with COI mutations. By optimizing methods of RC functional assessment, this research has the potential to
transform the evaluation of cellular respiratory disturbances in glaucoma. Associating disease risks with
haplogroup designations constitutes an important step towards individualized glaucoma treatment.
 The PI will conduct the research under the mentorship of experienced investigators from the University of
Pennsylvania (UPenn) and the Children's Hospital of Philadelphia. UPenn is an ideal setting for training
clinician-scientists, and the Scheie Eye Institute, in particular, is among the best in the country for research
training. The ophthalmology department is committed to fostering success, and has provided the PI with
protected time, dedicated space, institutional funds, and a nurturing environment. The PI has mastered multiple
techniques included in this proposal and has developed a comprehensive career development plan to facilitate
personal growth. By the end of the K award period, t...

## Key facts

- **NIH application ID:** 10219262
- **Project number:** 5K08EY029765-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Qi N Cui
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $227,417
- **Award type:** 5
- **Project period:** 2019-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10219262

## Citation

> US National Institutes of Health, RePORTER application 10219262, Mitochondrial Respiratory Chain Dysfunction in Primary Open Angle Glaucoma (5K08EY029765-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10219262. Licensed CC0.

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