Table 1.
Drugs and means targeting mitochondria to treat DR.
| Drugs or Means | Mitochondria Related Mechanisms and Targets | Effect in DR | Experimental Objects and Methods |
|---|---|---|---|
| Ubiquinone [161] | Promote electron transfer and ATP synthesis in mitochondrial respiratory chain | Improve mitochondrial function of platelets in patients with NPDR | Clinical trials |
| Short-Chain Quinones [177] | Antioxidant effect | Inhibit retinal ganglion cell loss, reactive glial hyperplasia, vascular leakage and retinal thinning | Animal Experiment (rat) |
| Zeaxanthin [178] | Inhibit the formation of lipid peroxides, maintain the activity of complex III and the level of mitochondrial SOD | Inhibit oxidative stress of retina | Animal Experiment (rat) |
| Lactucaxanthin [179] | Resist oxidation and restore mitochondrial membrane potential | Prevent the damage of RPE cells | Cell Experiment (ARPE-19) |
| Lutein [180,181] | Resist oxidation, restore mitochondrial membrane potential, enhance AMPK phosphorylation, and upregulate the expression of PGC-1α, NRF1 and TFAM, so as to maintain the integrity of mtDNA and normal mitochondrial biogenesis | Prevent the damage of RPE cells | Cell Experiment (ARPE-19) Animal Experiment (rat) |
| Lipoic acid [160,162] | Resist oxidation and prevent the formation of ROS | Prevent damage to microvessels and pericytes | Animal Experiment (rat) |
| N-acetylcysteine (+SS31,mitochondrial antioxidant) [182,183,184] | Enhance the interaction between cytochrome c, facilitate better electron transfer from complex III to complex IV, relieve mitochondrial dysfunction, oxidative stress and reduce mitophagic flux to lysosomes | Prevent the damage of RPE cells | Cell Experiment (ARPE-19) |
| Edaravone [185] | Clear ROS and restore mitochondrial membrane potential | Protect retinal ganglion cells | Cell Experiment (Primary Müller cell) |
| U83836E [186] | Restore the level of mitochondrial SOD and maintain the normal morphology of mitochondria | Improve the electrophysiological function of retinal ganglion cells, thereby relieving neurodegeneration in DR | Animal Experiment (rat) |
| Hydrogen sulfide donor GYY4137 [187] | Relieve oxidative stress, reduce MMP-9, and maintain mitochondrial integrity | Inhibit the apoptosis of RECs | Animal Experiment (mouse) Cell Experiment (HREC) |
| AMPK agonists (e.g., metformin) [188] | Restore mitochondrial membrane potential and abnormal morphology | Delay photoreceptor degeneration caused by diabetes | Animal Experiment (mouse) |
| Wnt inhibitory factor 1 [189] | Downregulate AMPK/mTOR pathway, improve mitochondrial function, restore mitochondrial membrane potential, and resist oxidation | Inhibit neovascularization and protect RPE cells | Cell Experiment (ARPE-19) Animal Experiment (mouse) |
| 670 nm photobiomodulation [190,191] | Increase the membrane potential and maintain the integrity of photoreceptor mitochondria | Protect Müller cells and photoreceptors from damage | Animal Experiment (mouse) Cell Experiment (rat Müller cell) Clinical trials |
| miR-451a [192] | Target ATF2 on the outer membrane of mitochondria to stabilize mitochondrial membrane potential and respiratory function | Inhibit the abnormal proliferation and migration of RPE cells in PDR | Cell Experiment (293T, ARPE-19) |
| Genipin [193] | Promote AKT signal pathway and regulate miR-4429/JAK2 signal axis | Maintain normal metabolism and membrane stability of mitochondria | Cell Experiment (APRE-19) |
| Notoginsenoside R1, NGR1 [121] | Enhance PINK1/Parkin dependent mitophagy | Alleviate the damage of Müller cells | Cell Experiment (rMC-1) |
| Taurine [194] | Reduce the expression of mitochondrial dependent apoptosis genes | Prevent retina cells from apoptosis | Animal Experiment (rat) |
| Polyphenols [159,170,195] | Inhibit the production of mitochondrial ROS and the expression of mitochondrial related pro-apoptotic factors; Adjust mTOR pathway | Inhibit the oxidative damage and apoptosis of optic nerve cells; Inhibit the formation of acellular capillaries and pericyte ghost; Promote autophagy and inhibit the apoptosis of Müller cells | Animal Experiment (mouse, rat) Cell Experiment (Primary rat Müller cell) |
| L-carnitine [163] | Reverse the change of mitochondrial membrane potential and the release of Cyt c; inhibit ROS production and lipid peroxidation; down-regulate apoptosis related proteins | Inhibit the apoptosis of retinal ganglion cells | Cell Experiment (Primary rat RGC) |
| Quercetin [196] | Promote the expression of antioxidant enzymes and inhibit the expression of mitochondrial related pro-apoptosis factors | Prevent diabetic retinal neurodegeneration and oxidative stress injury | Animal Experiment (rat) |
| Fenofibrate [165,167] | PPAR-α Agonists, inhibit mitochondrial ROS production | Inhibit the apoptosis of retinal vascular endothelial cells and pericyte loss | Cell Experiment (RF/6A) Animal Experiment (mouse) |
| hOGG1 [172] | Promote the repair of mtDNA damage | Inhibit the apoptosis of RECs | Cell Experiment (rREC) |
| GSK-3β inhibitor [197,198] | Inhibit the hyperphosphorylation of tau protein and maintain the normal transport and function of mitochondria in nerve cells | Regulate the apoptosis of retinal glial cells and inhibit synaptic neurodegeneration in early DR | Cell Experiment (Primary rat neurons and glial cells) |
| Hu-Zhang-Qing-Mai-Yin [199] | Increase p-P38 and ROS, decrease ATP level, and downregulate the expression of BCL-XL and BCL-2 | Promote mitochondrial apoptotic pathway of RECs | Cell Experiment (HRECs) |
| Astragalus Polysaccharide [200,201] | Adjust miR-182/Bcl-2 axis and miR-195/Bcl-2 axis to alleviate mitochondrial damage | Inhibit the apoptosis of RPEs | Cell Experiment (ARPE-19) |
| MTP-131 [169] | A novel mitochondrial targeting peptide that inhibits H2O2 induced mitochondrial damage and cytochrome c release | Prevent retinal ganglion cells from apoptosis | Cell Experiment (RGC-5) |
| E2 [168] | Stabilize mitochondrial membrane potential, reduce intracellular ROS level, up regulate Bcl-2 expression, inhibit Bax expression, and reduce the leakage of cytochrome c | Prevent retinal ganglion cells from apoptosis | Cell Experiment (RGC-5) |
| Exendin-4 [202] | Resist oxidation, downregulate NADPH, inhibit c-Jun N-terminal kinase, and downregulate protein kinase-β and p66Shc | Prevent mitochondrial apoptotic pathway of RPEs | Cell Experiment (ARPE-19) |
| TSHR-siRNA [203] | Block TSH receptors in retinal microvascular pericytes | Prevent mitochondrial apoptotic pathway of retinal pericytes | Cell Experiment (HRMVPCs) |
| Prohibitin (PHB) [204] | Inhibit ROS production and maintain mitochondrial homeostasis | Prevent RECs from apoptosis | Cell Experiment (HRECs) |
| Dixipamine [68] | Inhibit acid sphingomyelinase, inhibit the production of ceramide, and restore the normal metabolism of mitochondria | Restore normal function of RPEs | Animal Experiment (rat) |
| Simvastatin [166] | Upregulate PGC-1α and inhibit mitochondrial ROS/PARP pathway | Inhibit retinal vascular damage in early stage of diabetes | Animal Experiment (rat) |
| Tanshinone IIa [173] | Inhibit excessive fission of mitochondria and increase mRNA levels of mfn1 and opa1 | Inhibit methylglyoxal-induced injury of RECs | Cell Experiment (BREC) |
| Melatonin [175] | Downregulate the expression of mitochondrial fission related genes and upregulate the expression of mitochondrial biogensis related genes | Inhibit the apoptosis of RPEs and treat DME | Cell Experiment (ARPE-19) |
| Mdivi-1 [129] | Suppress PKC δ/Drp1 signal pathway and prevent excessive fission of mitochondria | Reverse retinal vascular leakage, acellular capillary formation and apoptosis | Cell Experiment (HRECs) |
| TGR5 [123] | Suppress PKC δ/Drp1 signal pathway and prevent excessive fission of mitochondria; regulate PINK1/Parkin signal pathway and enhance mitophagy | Inhibit the apoptosis of RECs | Cell Experiment (HREC) |
| Overexpress SIRT3 [124] | Activate mitophagy via Foxo3a/PINK1-Parkin pathway | Inhibit the apoptosis of RPEs | Cell Experiment (ARPE-19) |
| Penicillamine [176] | Chelate copper ions and increase the level of mitochondrial fusion protein mfn2 | Increase the activity of retinal pigment cells; inhibit ER stress and inflammation | Cell Experiment (ARPE-19) |
| SNGH16 [205] | Target miR-195 to increase the protein level of mfn2 | Inhibit pathological angiogenesis | Cell Experiment (HRECs) |