June 2020
Volume 61, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2020
Impaired Mitochondrial Glucose Metabolism and Fusion/Fission Dynamics in the Cone Photoreceptors of Mouse Models of Retinal Degeneration
Author Affiliations & Notes
  • Fan Yang
    Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Hongwei Ma
    Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Michael Butler
    Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Xi-Qin Ding
    Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Footnotes
    Commercial Relationships   Fan Yang, None; Hongwei Ma, None; Michael Butler, None; Xi-Qin Ding, None
  • Footnotes
    Support  National Eye Institute (R01EY019490 and P30EY12190) and the Oklahoma Center for the Advancement of Science and Technology
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 1294. doi:
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      Fan Yang, Hongwei Ma, Michael Butler, Xi-Qin Ding; Impaired Mitochondrial Glucose Metabolism and Fusion/Fission Dynamics in the Cone Photoreceptors of Mouse Models of Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2020;61(7):1294.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : The retina is one of the highest energy-consuming organs and thus requires a large number of mitochondria. There is growing evidence showing the association between mitochondrial dysfunction and retinal degenerations. Pyruvate dehydrogenase (PDH) and phosphoenolpyruvate carboxykinase (PEPCK) are critical mitochondrial enzymes that link glucose metabolism and tricarboxylic acid cycle. Mitochondrial dynamics including fusion and fission are critical for their function as well. This work investigated the alterations of mitochondrial PDH, PEPCK and fusion/fission dynamics in two mouse models of retinal degeneration.

Methods : The cyclic nucleotide-gated (CNG) channel-deficient and Leber Congenital Amaurosis Rpe65-deficient mouse models were used. The retinal localization and expression level and activity of PDH, PEPCK, and dynamin-related protein1 (Drp1) were evaluated by qRT-PCR, western blotting, RNAscope, and immunofluorescence. We further examined whether known protective strategies in these models, including cGMP/PKG signaling inhibition, endoplasmic reticulum (ER) calcium channel deletion, or type 2 iodothyronine deiodinase (Dio2) heterozygous deficiency, preserve cone viability by optimizing mitochondrial dynamics.

Results : Immunofluorescent staining showed that phospho-PDH was mainly localized in the retinal inner segment area, co-localizing with peanut agglutinin in cone photoreceptors. PEPCK staining was detected in outer nuclear layer by RNAScope. The protein expression levels of phospho-PDH, phospho-Drp1 (S637) and PEPCK were significantly increased in CNG channel-deficient mice and Rpe65-deficient mice. These elevations were greatly reduced in CNG channel-deficient mice with cGMP/PKG signaling inhibition or ER calcium channel deletion. Similarly, the elevated phospho-PDH and phospho-Drp1 (S637) levels were dramatically decreased in Rpe65-deficient mice with Dio2 heterozygous deficiency.

Conclusions : Our results showed that mitochondrial glucose metabolism and fusion/fission dynamics were altered in two mouse models of retinal degeneration. The manipulations leading to cone preservation reversed the alterations in these two models. These findings provide insights into mitochondrial dysfunction and retinal degenerations, as well as mechanisms of cone protection.

This is a 2020 ARVO Annual Meeting abstract.

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