Diabetic Retinopathy: The Role of Mitochondria in the Neural Retina and Microvascular Disease

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.

Stimulation of AMPK Prevents Diabetes-Induced Photoreceptor Cell Degeneration

“…AMPK can regulate mitochondrial function [26] and autophagy [27] in cells and plays an important role in the regulation of diabetes. In a high glucose environment, mitochondrial function is impaired, which leads to increased oxidative stress and changes in redox balance, thus affecting the structure and function of the retina [11].…”

“…In addition, mitochondrial function is closely associated with diabetic retinopathy [11]. Mitochondria are critical for energy production for metabolic activities, and their main functions include redox balance [12].…”

Therapeutical Management and Drug Safety in Mitochondrial Diseases—Update 2020

“…In fact, oxidative stress affects cell structures and components, particularly metabolically active neuronal cells such as photoreceptors. Therapies targeting these pathological processes were and are object of several studies in the literature [ 67 , 68 , 69 , 70 , 71 ].…”

TGF-β Serum Levels in Diabetic Retinopathy Patients and the Role of Anti-VEGF Therapy

“…Diabetic retinopathy (DR) is a complication of diabetes mellitus, and it is generally defined as the microvascular retinal complication of diabetes [ 1 , 2 ]. DR is clinically classified as non-proliferative (NPDR) and proliferative (PDR).…”