Abstract
Diabetic retinopathy (DR), a common chronic complication of diabetes mellitus and the leading cause of vision loss in the working-age population, is clinically defined as a microvascular disease that involves damage of the retinal capillaries with secondary visual impairment. While its clinical diagnosis is based on vascular pathology, DR is associated with early abnormalities in the electroretinogram, indicating alterations of the neural retina and impaired visual signaling. The pathogenesis of DR is complex and likely involves the simultaneous dysregulation of multiple metabolic and signaling pathways through the retinal neurovascular unit. There is evidence that microvascular disease in DR is caused in part by altered energetic metabolism in the neural retina and specifically from signals originating in the photoreceptors. In this review, we discuss the main pathogenic mechanisms that link alterations in neural retina bioenergetics with vascular regression in DR. We focus specifically on the recent developments related to alterations in mitochondrial metabolism including energetic substrate selection, mitochondrial function, oxidation-reduction (redox) imbalance, and oxidative stress, and critically discuss the mechanisms of these changes and their consequences on retinal function. We also acknowledge implications for emerging therapeutic approaches and future research directions to find novel mitochondria-targeted therapeutic strategies to correct bioenergetics in diabetes. We conclude that retinal bioenergetics is affected in the early stages of diabetes with consequences beyond changes in ATP content, and that maintaining mitochondrial integrity may alleviate retinal disease.
Highlights
Diabetes mellitus is a growing public health problem, reaching pandemic proportions in the United States and worldwide [1]
The importance of understanding the role of bioenergetics in the diabetic neural retina is supported by the knowledge that inherited mitochondrial diseases cause retinal disease and visual impairment [40], and is further highlighted by the heterogeneity of the neural retinal cells regarding the contribution of their mitochondria to cellular ATP and oxidative stress [41,42]
In comparison with heart, where the impact of individual components on the oxidative phosphorylation (Oxphos) and ATP synthesis has been determined, this control has yet to be investigated in the normal and diabetic retina. While it is unclear if complex III defect is limiting for the Oxphos in the diabetic retina, a decreased complex III activity led to increased superoxide in a mouse model of STZ-induced diabetes; both were normalized by overexpressing the mitochondrial antioxidant enzyme, manganese superoxide dismutase (MnSOD) [112]
Summary
Diabetes mellitus is a growing public health problem, reaching pandemic proportions in the United States and worldwide [1]. In addition to changes in the a- and b-waves on the ERG, alterations in the amplitude of the oscillatory potential (photopic and scotopic oscillatory potentials, which are initiated in the inner retina [19]) have been suggested to predict the progression of DR [20,21] In light of these findings, new discoveries into retinal physiology have emphasized the role of the neurovascular unit in DR [6], which refers to the physical and biochemical interaction between neurons (RGCs, amacrine cells, bipolar cells, and horizontal cells), glia (Müller cells and astrocytes), and the microvascular network (endothelial cells and pericytes) [22,23]. The importance of understanding the role of bioenergetics in the diabetic neural retina is supported by the knowledge that inherited mitochondrial diseases cause retinal disease and visual impairment [40], and is further highlighted by the heterogeneity of the neural retinal cells regarding the contribution of their mitochondria to cellular ATP and oxidative stress [41,42]. We will conclude by acknowledging emerging therapeutic approaches to correct mitochondrial bioenergetic-related functions and maintain the mitochondrial integrity in diabetes
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