Author ORCID Identifier

https://orcid.org/0000-0002-4814-7613

Semester

Spring

Date of Graduation

2023

Document Type

Dissertation

Degree Type

PhD

College

School of Pharmacy

Department

Pharmaceutical Sciences

Committee Chair

Jianhai Du

Committee Member

Roberta Leonardi

Committee Member

Lori Hazlehurst

Committee Member

John Hollander

Committee Member

Saravanan Kolandaivelu

Abstract

The retina and its neighboring retinal pigmented epithelium (RPE) are high energy-demanding and metabolically active tissues with specialized and complementary metabolism. They are metabolically interdependent and impact each other’s viability. Interestingly, many of the metabolic features in the retina and RPE are shared with the testis. For example, testis is also energy costly due to continuous sperm differentiation and it has similar metabolic inter-dependence between different testis cells. Both the retina and testis are vulnerable to mitochondrial metabolic impairments.

We conducted three research projects to understand 1) the nutrient utilization and communication in retina and RPE; 2) The profiling of metabolic proteins in retina and RPE during aging; 3) The role of isocitrate dehydrogenase 3B (IDH3B), a non-catalytic subunit of a key mitochondrial enzyme, in retina and testis. We found that: 1) RPE prefers proline as a nutrient, but retina has limited uptake of proline. Proline consumed by RPE is converted into many amino acids. Using 15N tracing coupled with mass spectrometry, we found RPE can utilize the nitrogen in proline to produce and export amino acids to the retina. 2) Aging impacts retina and RPE proteome differently: proteins involved in amino acid, sugar and lipid metabolism are substantially altered in the retina, while proteins in glycosaminoglycan degradation and lysosome metabolism are changed in the RPE. We also found aging changes the protein expressions and their ratio in RPE and retina, which constitutes the metabolic ecosystem in glucose and fatty acid metabolism. 3) We generated Idh3b-knockout (KO) mice and found that Idh3b-KO causes male infertility but not retinal degeneration in mice. Our investigation showed that loss of IDH3B causes an energetic deficit and disrupts sperm differentiation, highlighting the importance of the tissue-specific function of the ubiquitous tricarboxylic acid cycle.

Together, we uncover 1) proline nitrogen utilization in the retina and RPE, 2) the impact of aging on proteome, especially metabolic proteins in retina and RPE 3) the role of IDH3B in retinal health and sperm differentiation. We provided new insights into basic nutrient needs in the retina and RPE. Our research also provided a link between metabolism and retina/testis abnormalities.

Embargo Reason

Publication Pending

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