Rod metabolic demand drives progression in retinopathies

Abstract

Various factors are thought to cause the development and progression of disease in macular degeneration, diabetic retinopathy, and retinitis pigmentosa. Some of the deleterious processes include oxidative stress, hypoxia, metabolic derangement, genetics, and vasculopathy. In this review, we present a unified theory for the pathophysiology of several retinopathies based on the unique and intense metabolism of rod photoreceptors.

Keywords: SIRT6; diabetic retinopathy; macular degeneration; metabolism; retinitis pigmentosa.

Fig. 1

(A) In darkness, photoreceptor metabolism is similar to adult neurons. Glucose is catabolized through glycolysis, the TCA cycle, and oxidative phosphorylation, generating NAD+ and a large amount of ATP along with ROS. (B) In light, photoreceptor metabolism is similar to that of stem cells. Glucose undergoes glycolysis to form pyruvate, which is not further catabolized by the TCA cycle but is metabolized by the pentose phosphate pathway, generating several molecules of NADPH. NADPH is used for anabolic production of fatty acids, proteins, nucleic acids, and 11-cis retinal. ADP = adenosine diphosphate; ATP = adenosine triphosphate; HIF1 = hypoxia inducible factor 1; NFκB = nuclear factor kappa beta; PKM = pyruvate kinase muscle isozyme; ROS = reactive oxygen species; TCA = tricarboxylic acid; NADH = nicotinamide adenine dinucleotide (reduced); NAD+ = nicotinamide adenine dinucleotide (oxidized); PDH = pyruvate dehydrogenase; pAMPK = phosphorylated adenosine monophosphate activated protein kinase; NADPH = nicotinamide adenine dinucleotide phosphate; Ser = serine; Gly = glycine; GSSG = glutathione disulfide; GSH = glutathione.