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Jonathan Gong, Kun-Do Rhee, Xiang-Mei Zhang, Yanjie Wang, Xian-Jie Yang; Impact of Disrupting Lactate Dehydrogenase a (LDHa) on Retinal Metabolism and Photoreceptor Function. Invest. Ophthalmol. Vis. Sci. 2022;63(7):1781 – F0330.
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© ARVO (1962-2015); The Authors (2016-present)
The mature mammalian retina remains metabolically active to support visual function and life-long photoreceptor outer segment renewal. Recent studies suggest that rodent photoreceptors rely heavily on aerobic glycolysis for both energy supply and cellular anabolic activities. Lactate dehydrogenases are important enzymes that catalyze the bidirectional conversion between pyruvate and lactate. In this experimental study, we assess the impact of disrupting LDHa in both wild-type (WT) and degenerating retinas by performing molecular genetic and biochemical analyses.
Murine rod photoreceptor-specific LDHa gene deletion was conducted in both WT and Rds/Prph2(P216L) backgrounds using Rho-iCre. Perturbation of LDHa protein was detected using immunocytochemistry. LDH enzymatic activity assay was carried out in WT and Rds mutant retinas. Impact of LDHa rod deletion on the outer nuclear layer (ONL) was examined using rod and cone photoreceptor marker immunolabeling and confocal imaging. Visual function was assayed by electroretinography (ERG) at P51, P84, and P180.
Using an in situ enzymatic assay, the highest LDH activity was detected in the inner segment (IS) of retinal photoreceptors. Rod-specific deletion of LDHa gene resulted in the near abolishment of the LDH protein in the ONL without affecting its inner retina expression. In the WT background, deletion of LDHa in rods did not produce an apparent decrease in ONL thickness or visual function changes as measured by ERG. LDHa rod deletion did not appear to accelerate degeneration in the Rds mutant background. However, ERG detected significant deterioration of photopic b-wave. Furthermore, immunostaining detected abnormal cone cell morphological changes including exuberated opsin mislocalization and lateral dendritic sprouting.
These results show that LDHa is the major LDH enzyme expressed by photoreceptors. The main site for LDH activity in the retina is the photoreceptor IS, suggesting the proximity of LDHa protein localization with mitochondria in the photoreceptor IS. Further, rod-specific LDHa deletion can affect cone cell morphology and function in the Rds background. The apparent lack of disruption of photoreceptor morphology and function in the WT retina likely reflects the metabolic resilience and adaptability of the retinal network.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.
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