Role of Mitochondrial DNA Damage in the Development of Diabetic Retinopathy, and the Metabolic Memory Phenomenon Associated with Its Progression

Abstract

Diabetic retinopathy does not halt after hyperglycemia is terminated; the retina continues to experience increased oxidative stress, suggesting a memory phenomenon. Mitochondrial DNA (mtDNA) is highly sensitive to oxidative damage. The goal is to investigate the role of mtDNA damage in the development of diabetic retinopathy, and in the metabolic memory. mtDNA damage and its functional consequences on electron transport chain (ETC) were analyzed in the retina from streptozotocin-diabetic rats maintained in poor control (PC, glycated hemoglobin >11%) for 12 months or PC for 6 months followed by good control (GC, GHb < 6.5%) for 6 months. Diabetes damaged retinal mtDNA and elevated DNA repair enzymes (glycosylase). ETC proteins that were encoded by the mitochondrial genome and the glycosylases were compromised in the mitochondria. Re-institution of GC after 6 months of PC failed to protect mtDNA damage, and ETC proteins remained subnormal. Thus, mtDNA continues to be damaged even after PC is terminated. Although the retina tries to overcome mtDNA damage by inducing glycosylase, they remain deficient in the mitochondria with a compromised ETC system. The process is further exacerbated by subsequent increased mtDNA damage providing no relief to the retina from a continuous cycle of damage, and termination of hyperglycemia fails to arrest the progression of retinopathy.

Interleukin-1β and mitochondria damage, and the development of diabetic retinopathy

“…In the development of diabetic retinopathy, inflammatory mediators are elevated in the retina, mitochondria become dysfunctional, the enzyme important in scavenging superoxide is decreased and mtDNA becomes damaged [6,[11][12][13]15]. The present study demonstrates that amelioration of inflammatory mediators regulates mitochondrial damage and capillary cell apoptosis that the retina experiences in diabetes.…”

“…In addition, the release of cytochrome c from the mitochondria into the cytosol was quantified by western blot technique [13]. Damage of mtDNA was quantified by quantitative extended length PCR using mitochondrial genome-specific primers (Table 1), and to calculate relative amplification, the intensity of the long product (13.4 kb) was normalized with the short product (210 bp), as routinely used in our laboratory [11,12].…”

“…Cytochrome c leaks out of the mitochondria, accelerating the apoptosis of retinal capillary cells, and ultimately, resulting in the development of diabetic retinopathy [11][12][13]. Our previous work has shown that IL-1β, via increase in oxidative stress and activation of NF-kB, increases apoptosis of retinal capillary cells, and antioxidants, which inhibit the development of diabetic retinopathy in rodent models, also inhibit diabetesinduced increases in retinal IL-1β [4,14,15].…”

Glucose oscillations, more than constant high glucose, induce p53 activation and a metabolic memory in human endothelial cells

“…Mitochondrial DNA damage persists after glucose normalisation [42]. It is therefore possible that the persistent upregulation of oxidative stress and DNA damage markers, once the glucose level is normalised, might be caused by the action of p53 on the mitochondria and thereby be increased by glucose variability.…”

Oxidative Stress Biomarkers for Diabetic Retinopathy and Medical Management Affecting Oxidative Stress

“…H3K4me1/2/3 and H3K36me2/3 are generally associated with transcriptionally active genome regions, whereas H3K9me3, H3K27me3, and H4K20me3 are related with repressed domains [81]. In the development of DR, superoxide levels are elevated in the retina, antioxidant defense system is compromised, MnSOD is inhibited, and mitochondria are swollen and dysfunctional [77,[87][88][89][90]. Overexpression of MnSOD protects diabetesinduced mitochondrial damage and the development of DR [19,91].…”