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Mitochondrial Stability in Diabetic Retinopathy: Lessons Learned from Epigenetics

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Mitochondrial Stability in Diabetic Retinopathy: Lessons Learned from Epigenetics Diabetes Volume 68, February 2019 241 Mitochondrial Stability in Diabetic Retinopathy: Lessons Learned From Epigenetics Renu A. Kowluru Diabetes 2019;68:241–247 | https://doi.org/10.2337/dbi18-0016 Diabetic retinopathy remains the leading cause of ac- With time, preretinal hemorrhage and neovascularization quired blindness in working-age adults. While the cutting- begin to appear, and if not treated, the retina detaches, edge research in the field has identified many leading to blindness. The pathogenesis of the disease is molecular, functional, and structural abnormalities, the strongly associated with the duration of diabetes, and exact molecular mechanism of this devastating disease uncontrolled blood glucose is considered as the primary remains obscure. Diabetic environment drives dysfunc- driving factor; however, blood pressure and hyperlipid- tion of the power generator of the cell and disturbs the emia also play significant roles in its development. Although PERSPECTIVES IN DIABETES homeostasis of mitochondrial dynamic. Mitochondrial the clinical pathology of diabetic retinopathy is mainly DNA (mtDNA) is damaged, the transcription of mtDNA- observed in the retinal microvasculature, recent evidence encoded genes is impaired, and the electron transport has clearly demonstrated neurodegeneration as an early chain is compromised, fueling into a vicious cycle of free event in the pathogenesis of this blinding disease (2,3). radicals. The hyperglycemic milieu also alters the epige- High glucose initiates a whole array of molecular, bio- netic machinery, and mtDNA and other genes associated with mitochondrial homeostasis are epigenetically mod- chemical, and functional abnormalities affecting many ified, further contributing to the mitochondrial damage. metabolic pathways including activation of protein kinase Thus, mitochondria appear to have a significant role in C, increased production of advanced glycation end prod- the development of diabetic retinopathy, and unravel- ucts, and polyol and hexosamine pathways. Auto-oxidation ing the mechanism responsible for their damage as of glucose, and/or initiation of many metabolic abnormal- well as the role of epigenetic modifications in mito- ities, in the hyperglycemic milieu increases the levels of chondrial homeostasis should identify novel therapeutic reactive oxygen species (ROS) in the retina, creating an targets. This will have a major impact on inhibiting/ environment with excessive free radicals (4,5). Mitochon- halting diabetic retinopathy and preventing the loss of dria are the sites of cellular respiration, a process that vision. ultimately generates fuel for the cell. During oxidative phosphorylation, the respiratory chain utilizes ;95% of the oxygen in aerobic animals to produce ATP. However, Diabetic retinopathy is the leading cause of vision loss 1–5% of all oxygen used in complexes I and III of the among working-age adults in the industrialized nations. electron transport chain (ETC) escapes as superoxide One-third of patients with diabetes have some form of radicals, making mitochondria the organelle with high retinopathy, and among those 10% develop a vision- ROS and also a target for the damaging free radicals. threatening form of the disease. Worldwide, ;127 million The majority of superoxide radicals are quickly converted people were diagnosed with diabetic retinopathy in 2010, to diatomic oxygen and hydrogen peroxide by mitochon- and with the incidence of diabetes increasing at a very fast drial manganese superoxide dismutase (Sod2). Under nor- pace, over 190 million people are expected to be affected by mal physiological conditions, free radicals are important this blinding disease in 2030 (1). for many cellular processes including cell signaling, apo- Diabetic retinopathy is a progressive disease; micro- ptosis, and phagocytosis, but increased accumulation of aneurysms and deposits may appear in the retina, but the these dangerous radicals induces oxidative stress. In many disease remains largely asymptomatic in the initial stages. diseases, including diabetic retinopathy, oxidative stress, Kresge Eye Institute, Wayne State University, Detroit, MI © 2019 by the American Diabetes Association. Readers may use this article as fi Corresponding author: Renu A. Kowluru, [email protected] long as the work is properly cited, the use is educational and not for pro t, and the work is not altered. More information is available at http://www.diabetesjournals Received 28 August 2018 and accepted 6 November 2018 .org/content/license. 242 Mitochondria and Diabetic Retinopathy Diabetes Volume 68, February 2019 resulting from an imbalance between the production of initiation and replication. Biogenesis of mtDNA requires ROS and their compensation, is considered one of the key a coordinated synthesis of nuclear and mitochondrial drivers for cellular dysfunction and loss (6). encoded proteins and mtDNA replication and is dependent mainly on mtDNA polymerase g (POLG), master transcrip- MITOCHONDRIAL QUALITY CONTROL tion factor A (TFAM), and transcription factor B2 (13). Mitochondria have elongated structure, bounded by a double membrane, and while the outer mitochondrial MITOCHONDRIA AND DIABETIC RETINOPATHY membrane has integral proteins, porins, that allow small As mentioned above, mitochondria have an important molecules to pass into the mitochondria, the inner mem- function to preserve cell integrity, and any defect in brane has cristae. Mitochondria are highly dynamic organ- this powerhouse is detrimental to cell functioning and elles, and to maintain proper functioning, intracellular survival. Diabetic retinopathy is a slow-progressing mul- quality control of mitochondria is maintained by fission, tifactorial complication, and increased oxidative stress has fusion,mitophagy,andbiogenesis.Mitochondrialeffi- been shown to play a major role in its development (2,4,5). fl ciency re ects the net balance between two opposing The retina is a highly metabolic tissue in the body, and due fi fi processes, ssion and fusion. While ssion is characterized to high circulating glucose, electron flux through ETC is by the division of one mitochondrion into two daughter increased and the activity of complex III is reduced, mitochondria, fusion unites two mitochondria into one culminating in increased accumulation of ROS (14). Ret- mitochondrion and dilutes injured mitochondrial proteins inal mitochondria are damaged and their ultrastructure and DNA by mixing their contents. Fusion promotes the shows partial cristolysis, their membrane integrity is im- formation of elongated mitochondria with capacity to paired and cytochrome c leaks out into the cytosol, and produce more ATP (7). Outer membrane fusion is medi- mtDNA copy numbers are decreased. To make the bad ated by fusion proteins, mitofusin 1 and 2 (Mfn1 and situation worse, cytosolic ROS-producing enzymes NADPH Mfn2), and inner membrane fusion is mediated by optic oxidases are also activated, and constant hammering by atrophy protein 1 (OPA1). Both Mfn1 and Mfn2 share the cytosolic ROS damages mitochondrial integrity, fueling ;80% similarity and have the same structural motifs. into a vicious cycle of free radicals (5,15,16). Increased Mfn2, however, has a proline-rich region that tethers to ROS also activate gelatinase matrix metalloproteinase fi the mitochondria and is suf cient and essential to modulate 9 (MMP-9), and activated MMP-9, with the help of heat fi mitochondrial metabolism. The ssion protein, dynamin- shock proteins, is translocated inside the mitochondria. related protein 1 (Drp1), constricts mitochondrial mem- This results in the breakdown of mitochondrial mem- fi branes in a GTP-dependent manner (8). Fusion and ssion branes and initiation of the apoptotic process (17). In occur almost simultaneously, and unhealthy mitochondria a normal situation, ROS generation is kept under control are segregated for turnover by the autophagosomal path- by endogenous antioxidants like glutathione (GSH), Sod, way mitophagy (9). Microtubule-associated protein light and catalase, but the suboptimal cytosolic and mitochon- chain 3 (LC3), a common autophagy marker, is expressed drial antioxidant redox system in diabetes further exacer- at a basal level, but in pathological conditions, it is pro- bates the damage (5,15,16). teolytically cleaved to LC3II during autophagy. Accumula- As mentioned above, mitochondria contain several tion of PTEN-induced putative kinase 1 (PINK1) at the copies of the circular DNA, and their close proximity to outer membrane of depolarized mitochondria allows re- ROS makes this histone-free “naked” DNA vulnerable to cruitment of the E3 ubiquitin ligase Parkin. This polyubi- free radical damage. In diabetes, the levels of oxidized quitinates proteins on the outer mitochondrial membrane nucleoside 8-hydroxy-2-deoxy-guanosine (8-OHdG) are and degrades the damaged mitochondria, and biogenesis increased in the mitochondria, and mtDNA shows in- replenishes mitochondrial mass (10). Defective mitochon- creased sequence variants. The D-loop region shows drial dynamic has been implicated in many chronic more damage and sequence variants than other coding diseases, including cancer and diabetes (11). regions of the mtDNA. The transcription of mtDNA is impaired, and the ETC system is further compromised MITOCHONDRIAL GENOME (5,16). Mitochondria have an efficient system to repair Thenucleusisthemainsiteofgenetranscription,and DNA damage consisting of base excision repair enzyme mitochondria are the only other subcellular component
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