Mitochondrial Stability in Diabetic Retinopathy: Lessons Learned From Epigenetics

Abstract

Diabetic retinopathy remains the leading cause of acquired blindness in working-age adults. While the cutting-edge research in the field has identified many molecular, functional, and structural abnormalities, the exact molecular mechanism of this devastating disease remains obscure. Diabetic environment drives dysfunction of the power generator of the cell and disturbs the homeostasis of mitochondrial dynamic. Mitochondrial DNA (mtDNA) is damaged, the transcription of mtDNA-encoded genes is impaired, and the electron transport chain is compromised, fueling into a vicious cycle of free radicals. The hyperglycemic milieu also alters the epigenetic machinery, and mtDNA and other genes associated with mitochondrial homeostasis are epigenetically modified, further contributing to the mitochondrial damage. Thus, mitochondria appear to have a significant role in the development of diabetic retinopathy, and unraveling the mechanism responsible for their damage as well as the role of epigenetic modifications in mitochondrial homeostasis should identify novel therapeutic targets. This will have a major impact on inhibiting/halting diabetic retinopathy and preventing the loss of vision.

Faulty homocysteine recycling in diabetic retinopathy

“…Mitochondrial homeostasis plays an important role in the pathogenesis of diabetic retinopathy, and experimental models have shown impaired mitochondrial dynamics [2][3][4][5]. Homocysteine plays a crucial role in reducing mitochondrial respiration and damaging the mitochondrial fusion-fission process [48].…”

“…Many molecular mechanisms have been implicated in its development, but despite ongoing cutting edge research in the field, the molecular mechanism of this multi-factorial disease is still not clear [1]. In the pathogenesis of diabetic retinopathy, oxidative stress is increased in the retina and its vasculature, mitochondria are damaged and have impaired homeostasis, gene transcription associated with oxidative stress are altered, and apoptosis of capillary cells are accelerated [2][3][4][5].…”

Epigenetic Control of Mitochondrial Function in the Vasculature

“…Recent evidence indicates that epigenetic changes, defined as plastic modifications of DNA/histone complexes, are heavily implicated in the regulation of mitochondrial and vascular function (52,53). Studies conducted over the last few years have unmasked a complex intersection among environmental factors, mitochondrial metabolism, epigenetic signals and transcriptional programs (54,55).…”

“…Studies conducted over the last few years have unmasked a complex intersection among environmental factors, mitochondrial metabolism, epigenetic signals and transcriptional programs (54,55). Epigenetic changes acquired during the life time may derail the expression of genes involved in mitochondrial homeostasis (52). On the other hand, metabolic alterations occurring in mitochondria may affect the availability of substrates for chromatin-modifying enzymes, thus leading to maladaptive epigenetic signatures altering chromatin accessibility and, hence, gene transcription (Figure 2) (54).…”

Epigenetics and Mitochondrial Stability in the Metabolic Memory Phenomenon Associated with Continued Progression of Diabetic Retinopathy

“…extensive at its D-loop, the region with critical transcription and replication sites 11,15,16 . Sequence variants are significantly increased in the already heteroplasmic mtDNA, and the bad situation is further worsened by suboptimal levels of the mtDNA repair enzyme MutL homolog 1, Mlh1, which is responsible to cut these mismatches 17 .…”