Author ORCID Identifier

https://orcid.org/0000-0001-5991-813X

Semester

Summer

Date of Graduation

2026

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Biochemistry

Committee Chair

Jianhai Du

Committee Member

John M Hollander

Committee Member

Roberta Leonardi

Committee Member

Saravanan Kolandaivelu

Committee Member

Wen Tao Deng

Abstract

Ornithine aminotransferase (OAT) is a mitochondrial enzyme that regulates ornithine metabolism by converting ornithine to pyrroline-5-carboxylate, a precursor for proline and glutamate synthesis. Deficiency of OAT causes systemic ornithine accumulation and leads to gyrate atrophy (GA) of the choroid and retina, a hereditary disorder characterized by progressive chorioretinal degeneration and irreversible vision loss. Chorioretinal atrophy typically starts at the mid-peripheral retina and progresses toward the macula. Although elevated ornithine is considered toxic to the eye, how ornithine is metabolized in ocular tissues and why OAT deficiency causes selective, region-specific vulnerability remain unclear. We combined ex vivo and in vivo stable isotope tracing, targeted metabolomics, and quantitative proteomics in mouse liver, retina, and retinal pigment epithelium/choroid (RPE/Cho), together with human RPE/Cho explants from the macula, mid-periphery, and far periphery, to define the metabolic role of OAT in ocular tissues. We found that in addition to high circulating ornithine levels, OAT deficiency caused marked intracellular ornithine accumulation in the RPE/Cho, retina, and liver, and induced tissue-specific metabolic and proteomic remodeling in the early phases prior to retinal degeneration. In ocular tissues, RPE/Cho showed the strongest molecular response, including broad changes in mitochondrial, cytoskeletal, and extracellular matrix proteins, whereas the retina showed early changes dominated by perturbed amino acid metabolism. In the liver, excess ornithine was redirected toward the urea cycle and was associated with altered detoxification, redox, and methylation-related pathways. Stable isotope tracing showed that RPE/Cho uses ornithine carbon and nitrogen through OAT to generate proline, glutamate, aspartate, and tricarboxylic acid cycle intermediates, whereas the retina uses ornithine mainly for proline synthesis. Loss of OAT disrupted these pathways and altered amino acid, nucleotide, and energy metabolism in ocular tissues. In human RPE/Cho explants, the mid-periphery showed the greatest metabolic sensitivity to elevated ornithine, followed by the far periphery, whereas the macula was the least affected region. OAT inhibition alone had minimal effects in the peripheral explants. Combining OAT inhibition with elevated ornithine produced a GA-like metabolic state marked by increased ornithine, arginine, and citrulline, decreased proline, and altered lysine catabolism, with stronger effects in the mid-periphery than in the far periphery. Together, these findings establish OAT as a key regulator of tissue- and region-specific metabolic homeostasis in ocular tissues and support that GA results from the combined effects of excess ornithine and loss of local OAT-dependent metabolism. This work provides a foundation for understanding the role of OAT and ornithine metabolism in ocular tissues and developing future therapies to prevent degeneration in GA.

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