Research, led by scientists at the Kresge Eye Institute, Wayne State University, Michigan, has shown that mitochondrial DNA methylation is affected by high glucose levels leading to apoptotic cell death in the retina. As capillary cell apoptosis precedes the hallmark retinal histopathology characteristic of diabetic retinopathy, any opportunity to halt such cell death may positively impact on disease progression. Having shown the impact of mtDNA methylation on the disease process, the US research team used short-interfering RNA (siRNA) or pharmacologic inhibitors targeting DNA methyl-transferases (Dnmts) to restore mitochondrial homeostasis. Further refinement of the approach may facilitate the development of therapeutic approaches to inhibit the progression of diabetic retinopathy.
Given the alarming global increase in diabetes, and the consequent increase in the incidence of diabetic retinopathy, a significant increase in the volume of research is now aimed at exploring new avenues for both earlier diagnosis and treatment of the growing epidemic. The Michigan study focused on the extra-chromosomal mitochondrial DNA comprised of 37 genes, 13 of which are primarily involved in oxidative phosphorylation mediated by the electron transport chain. DNA methylation is a well-characterized biological process, enhanced within the diabetic environment, in which methyl-transferases methylate CpG dinucleotides leading to down-regulation of mitochondrial gene expression. With the activity of methyl-transferases increased in diabetes, the impact on gene expression leads to cellular dysfunction which then triggers mitochondrial driven apoptosis. The US research examined the Dnmt1 gene, responsible for DNA methlylation, and in particular used inhibitors to block its activity.
Using cells isolated from the bovine retinal endothelium layer, cultured cells were exposed to high glucose (20 mM) levels to record the impact of the altered environment on mtDNA methylation. The role of the mtDNA methylation in both gene transcription and apoptotic cell death was tracked and cells transfected with Dnmt1-small interfering RNA (siRNA) were assessed to determine if the process could be attenuated in any way. Results from the study showed that high glucose levels increased mtDNA methylation and was associated with an increased mitochondrial accumulation of Dnmt1. Most interesting from a therapeutic perspective was that inhibition of the DNA methyl-transferases at the genetic level using siRNA, or at the protein level by pharmacologic inhibitors, appeared to ameliorate methylation activity and reduce apoptotic cell apoptosis. In conclusin, the researchers suggest that “regulation of mtDNA methylation has potential to restore mitochondrial homeostasis and inhibit/retard the development of diabetic retinopathy”.