Abstract
Purpose :
We previously report mitochondrial pyruvate transporter is essential for retinal metabolism and visual function. Mitochondrial pyruvate can be oxidized into acetyl-CoA or carboxylated into oxaloacetate through pyruvate carboxylase (PC) to feed the tricarboxylic acid cycle (TCA cycle). This study aims to elucidate the role of PC in retinal metabolism and visual function.
Methods :
We created knockout (KO) mice with retina-specific PC deficiency and validated the expression of PC through immunoblot and immunofluorescence. Retinal metabolism was examined using targeted metabolomics. Visual function and retinal morphology were assessed through electroretinogram (ERG) and Optical coherence tomography (OCT) and hematoxylin and eosin (H&E) staining on eye sections.
Results :
PC is predominantly expressed in Müller glial cells and inner neurons. Retinal deletion of PC causes 1.2~1.9 fold reduction of various mitochondrial intermediates (oxaloacetate, malate, aspartic acid, α-ketoglutarate, citrate, succinate and aconitate), antioxidants (glutathione and carnosine), and as well as intermediates in branch-chain amino acid and lysine catabolism. Surprisingly, scotopic and photopic ERGs and retinal morphology remained normal within 12 months. However, photopic b wave exhibits a significant decreased in PC KO mice after 24 or 48 hours of fasted but not their littermate controls, suggesting PC plays a crucial role in maintaining metabolic reserve for the function of cone photoreceptors.
Conclusions :
The carboxylation of mitochondrial pyruvate in Müller glial and inner neurons finely regulates the pool sizes of mitochondrial intermediates, synthesis of antioxidants and amino acid catabolism, which is critical for cone function.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.