Glutaminase deficiency in rod photoreceptors disrupts nonessential amino acid levels to activate the integrated stress response and induce rapid degeneration.

Glucose has been central in the study of photoreceptor cell metabolism. Recently, it was shown that fuel sources besides glucose can meet the metabolic needs of photoreceptors. Glutamine (Gln) is the most abundant circulating amino acid and has many biosynthetic and bioenergetic roles in cells. Glutaminolysis is the process by which Gln is metabolized into tricarboxylic acid cycle intermediates to provide biosynthetic precursors. Here, Gln is first converted to glutamate via the enzyme glutaminase (GLS). This research demonstrates that deletion of GLS in rod photoreceptors alters retinal metabolism, activates the integrated stress response (ISR), and results in rapid photoreceptor degeneration. As such, Gln is a critical fuel source that supports photoreceptor cell biomass, redox balance, and survival.