# SLC4A11 Mitochondrial Uncoupling and ROS Production in Corneal Endothelium

> **NIH NIH R01** · TRUSTEES OF INDIANA UNIVERSITY · 2021 · $412,046

## Abstract

“SLC4A11 Mitochondrial Uncoupling and ROS Production in Corneal Endothelium”
ABSTRACT
 Defects in the gene SLC4A11 cause Congenital Hereditary Endothelial Dystrophy and some forms of
Fuchs Dystrophy. The goal of this study is to understand the role of this membrane transporter in normal corneal
endothelial metabolism and how SLC4A11 deficiency leads to Corneal Dystrophy. The corneal endothelial
“pump” maintains corneal hydration and transparency. When the “pump” fails due to trauma, inflammation,
ageing, or dystrophy, corneal edema ensues, transparency is lost, and vision is significantly degraded. The usual
therapy is transplantation, which is not without significant compromises and complications. A hallmark of Corneal
Endothelial Dystrophies is mitochondrial dysfunction. Our laboratory has shown that SLC4A11 is an NH3
dependent electrogenic H+ transporter. We have found that glutamine is actively metabolized by the endothelium
producing NH3 and enhancing ATP formation. Slc4a11 knock out shows significant corneal edema, lactate
accumulation, altered mitochondrial physiology, and ROS. These data have led to the overarching hypothesis
that corneal endothelium actively metabolize glutamine and that the absence of SLC4A11 alters glutamine
metabolism, leading to mitochondrial dysfunction, ROS, and eventual apoptosis. Preliminary data indicate that
SLC4A11 is both a plasma membrane and a mitochondrial membrane protein, leading to the novel hypothesis
that SLC4A11 is a mitochondrial uncoupler. Using multiple in vitro & in vivo complementary approaches these
hypotheses will be tested in three aims. Aim 1 will determine how glutamine metabolism is facilitated in Corneal
Endothelial mitochondria. The hypothesis is that Slc4a11 is an NH3 sensitive mitochondrial uncoupler that works
in conjunction with Uncoupling Protein-2 and the potential mitochondrial buffer taurine to facilitate Glutamine
catabolism. Aim 2 will examine the source of ROS and ROS as a stimulus to Apoptosis in Slc4a11 KO. Our
hypothesis is that apoptosis is accelerated by ROS, which is generated by the interaction of NH3 with an
energized electron transport chain and reduced by SLC4A11 uncoupling. Aim 3 will identify the cause of corneal
edema in Slc4a11 KO Mice. We will test the hypothesis that loss of Slc4a11 secondarily induces downregulation
of key proteins that facilitate lactate transport. Completion of this study will establish the role of SLC4A11 and
glutamine in endothelial metabolism; provide new insight for mechanisms that facilitate glutamine metabolism
yet alleviate NH3 induced ROS production that will be transferable to a wide array of glutamine metabolizing
tissues; and provide insight for development of therapies for endothelial dystrophies.

## Key facts

- **NIH application ID:** 10141240
- **Project number:** 5R01EY031321-02
- **Recipient organization:** TRUSTEES OF INDIANA UNIVERSITY
- **Principal Investigator:** Joseph Aurelio Bonanno
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $412,046
- **Award type:** 5
- **Project period:** 2020-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10141240

## Citation

> US National Institutes of Health, RePORTER application 10141240, SLC4A11 Mitochondrial Uncoupling and ROS Production in Corneal Endothelium (5R01EY031321-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10141240. Licensed CC0.

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