Glutaminolysis is Essential for Energy Production and Ion Transport in Human Corneal Endothelium

Abstract

Corneal endothelium (CE) is among the most metabolically active tissues in the body. This elevated metabolic rate helps the CE maintain corneal transparency by its ion and fluid transport properties, which when disrupted, leads to visual impairment. Here we demonstrate that glutamine catabolism (glutaminolysis) through TCA cycle generates a large fraction of the ATP needed to maintain CE function, and this glutaminolysis is severely disrupted in cells deficient in NH ₃:H ⁺ cotransporter Solute Carrier Family 4 Member 11 (SLC4A11). Considering SLC4A11 mutations leads to corneal endothelial dystrophy and sensorineural deafness, our results indicate that SLC4A11-associated developmental and degenerative disorders result from altered glutamine catabolism. Overall, our results describe an important metabolic mechanism that provides CE cells with the energy required to maintain high level transport activity, reveal a direct link between glutamine metabolism and developmental and degenerative neuronal diseases, and suggest an approach for protecting the CE during ophthalmic surgeries.

Graphic Abstract

Highlights

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  Glutamine contributes half of TCA cycle intermediates in human corneal endothelium.

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  Glutamine catabolism supplies significant ATP that fuels the endothelial pump function.

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  SLC4A11 (NH ₃:2H ⁺ cotransporter) knockout shows ammonia related oxidative damage.

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  Loss of SLC4A11 transporter disrupts expression of glutaminolysis enzymes.

The corneal endothelium (CE) is responsible for maintaining corneal transparency through the action of active transport processes. We report that CE metabolizes the amino acid glutamine producing ATP in support of active transport. In the mouse model of CHED (Congenital Hereditary Endothelial Dystrophy), which manifests corneal edema and loss of transparency, glutamine metabolism is disrupted due to loss of SLC4A11, an NH ₃:2H ⁺ transporter. This work sheds light on potential clinical therapies to facilitate CE function, the pathogenesis of CHED and Fuchs' Endothelial Corneal Dystrophy, and suggests that the ammonia handling capacity of SLC4A11 is essential for efficient metabolism of glutamine.