Therapeutic targets for altering mitochondrial dysfunction associated with diabetic retinopathy

Abstract

Retinopathy remains as one of the most feared blinding complications of diabetes, and with the prevalence of this life-long disease escalating at an alarming rate, the incidence of retinopathy is also climbing. Although the cutting edge research has identified many molecular mechanisms associated with its development, the exact mechanism how diabetes damages the retina remains obscure, limiting therapeutic options for this devastating disease. Areas covered: This review focuses on the central role of mitochondrial dysfunction/damage in the pathogenesis of diabetic retinopathy, and how damaged mitochondria initiates a self-perpetuating vicious cycles of free radicals. We have also reviewed how mitochondria could serve as a therapeutic target, and the challenges associated with the complex double mitochondrial membranes and a well-defined blood-retinal barrier for optimal pharmacologic/molecular approach to improve mitochondrial function. Expert opinion: Mitochondrial dysfunction provides many therapeutic targets for ameliorating the development of diabetic retinopathy including their biogenesis, DNA damage and epigenetic modifications. New technology to enhance pharmaceuticals uptake inside the mitochondria, nanotechnology to deliver drugs to the retina, and maintenance of mitochondrial homeostasis via lifestyle changes and novel therapeutics to prevent epigenetic modifications, could serve as some of the welcoming avenues for a diabetic patient to target this sight-threatening disease.

Retinoprotection by BGP-15, a Hydroximic Acid Derivative, in a Type II Diabetic Rat Model Compared to Glibenclamide, Metformin, and Pioglitazone

“…to promoter of matrix metalloproteinase 9 (MMP9), which results in transactivation and eventually leads to mitochondrial damage [15] probably in the diabetic retina as well. Mitochondrial damage and eventual death of retinal cells may lead to the deterioration of visual function, a characteristic symtpom of diabetic retinopathy [17]. Whether BGP-15 may affect in this pathway beside HSP72 either SIRT1 or MMP9 and thus the pathogenesis of diabetic retinopathy was still to be discovered.…”

Resolvin D1 reduces mitochondrial damage to photoreceptors of primary retinal cells exposed to high glucose

“…MMPs (Kowluru & Mishra, 2018). Particularly, the activation of MMP-9 by the conversion of the thiol group to sulfinic acid by ROS (Nelson & Melendez, 2004;Touyz, 2006), together with the activation of MMP-2, is an early event that precedes mitochondrial damage (Kowluru & Mishra, 2018). Moreover, FPR2 receptor deficiency has been recently correlated to the MMP-9 increase in abdominal aortic aneurysms (Petri et al, 2018).…”

“…Moreover, RvD1 improved mitochondrial function by reducing NADH levels, and by restoring TIMM44, TOM 40 and OGG1 expression. These are mitochondrial transporters and mtDNA repair system activated once excessive ROS damage the electron transport chain (ETC) by causing electron leakage (Kowluru & Mishra, 2018 (Du, Miller, & Kern, 2003;Nita & Grzybowski, 2016).…”

“…Diabetic retinopathy (DR), the primary cause of blindness in the working‐age population (Klein, ) and a microvascular complication of diabetes, is triggered by inflammatory processes underlying early and late stages of retinal damage (Rübsam, Parikh, & Fork, ). High glucose levels, by resulting in multiple oxidative cellular pathways and excessive generation of reactive oxygen species (ROS), lead to mitochondrial dysfunction in the early stages of retinal diabetic damage, which play a pivotal role in retinal cell apoptosis (Kowluru & Mishra, ; Santos, Tewari, Lin, & Kowluru, ; Song et al, ; Stitt, ). Besides mitochondrial DNA (mtDNA) damage and decreased mitochondrial copy numbers (Mishra & Kowluru, ; Santos, Tewari, Goldberg, & Kowluru, ), retinal mitochondria dysfunction induced by diabetes generated ROS is associated also with activation of retinal matrix metalloproteinases (MMP‐9 and MMP‐2) (Santos et al, ).…”

Flavoprotein Fluorescence Correlation with Visual Acuity Response in Patients Receiving Anti‐VEGF Injection for Diabetic Macular Edema

“…DR is due to a complex interplay of multiple pathways leading to increased aldose reductase, protein kinase C, and hexosamine pathway activities, glycation of proteins, nitrosylation, and damage to both nuclear and mitochondrial DNA [ 17 – 19 ]. All of these perturbations may be linked to mitochondrial depolarization, dysfunction, and damage with the associated generation of superoxides and other free radicals [ 17 , 18 , 20 , 21 ]. Mitochondrial dysfunction is recognized to be at the pathogenetic core of inflammation, apoptosis, and response to hyperglycemia in DR. [ 6 , 7 , 17 – 19 ]…”