Diabetic Retinopathy: Mitochondria Caught in a Muddle of Homocysteine

Abstract

Diabetic retinopathy is one of the most feared complications of diabetes. In addition to the severity of hyperglycemia, systemic factors also play an important role in its development. Another risk factor in the development of diabetic retinopathy is elevated levels of homocysteine, a non-protein amino acid, and hyperglycemia and homocysteine are shown to produce synergistic detrimental effects on the vasculature. Hyperhomocysteinemia is associated with increased oxidative stress, and in the pathogenesis of diabetic retinopathy, oxidative stress-mitochondrial dysfunction precedes the development of histopathology characteristic of diabetic retinopathy. Furthermore, homocysteine biosynthesis from methionine forms S-adenosyl methionine (SAM), and SAM is a co-substrate of DNA methylation. In diabetes, DNA methylation machinery is activated, and mitochondrial DNA (mtDNA) and several genes associated with mitochondrial homeostasis undergo epigenetic modifications. Consequently, high homocysteine, by further affecting methylation of mtDNA and that of genes associated with mtDNA damage and biogenesis, does not give any break to the already damaged mitochondria, and the vicious cycle of free radicals continues. Thus, supplementation of sensible glycemic control with therapies targeting hyperhomocysteinemia could be valuable for diabetic patients to prevent/slow down the development of this sight-threatening disease.