Metabolic Disorder leads to Retinal degeneration: Function, morphology and metabolic pathway analysis.

Abstract

INTRODUCTION The retina prefers to metabolize glucose through glycolysis rather than oxidative phosphorylation (OXPHOS) to meet their energy demand even when oxygen is abundant, known as the “Warburg effect”, despite having abundant functional mitochondria. We created transgenic mice with selective knockdowns of key enzymes in glycolysis and OXPHOS including hexokinase (HK) 2, lactate dehydrogenase (LDH) A and pyruvate dehydrogenase (PDH) E1α in rods to study the importance of glycolysis and OXPHOS in retinal metabolism and the role of metabolic derangement in the pathogenesis of retinal diseases.

MATERIALS AND METHODS Immunohistochemistry and Western blots were performed to study the changes in protein expression and regulation. Scotopic electroretinography and optical coherence tomography were performed to study the retinal function and structure. Gas and liquid chromatography-mass spectrometry were employed to study the changes in13C-glucose-derived metabolites in the retina.

RESULTS Knockdown of HK2 in rods led to photoreceptor degeneration, with reduction in the thickness of the retina and impaired retinal function. Knockdown of HK2 decreased pyruvate production but promoted the tricarboxylic acid (TCA) cycle in the retina.

Knockdown of LDHA and PDHE1α in rods also led to retinal degeneration, with thinning of the retina and impaired retinal function. Deletion of LDHA and PDHE1α suppressed glycolysis and the TCA cycle in the retina.

CONCLUSION We found that HK2/LDHA-mediated glycolysis and PDHE1α mediated-OXPHOS in rods are indispensable for the maintenance of photoreceptor structure and function. Disturbance in aerobic glycolysis or OXPHOS leads to metabolic remodelling in the retina and photoreceptor degeneration.