TABLE 3.
Potential therapeutics for RPE Aging and AMD through restoring mitochondrial function.
| Compound | Functions | References |
|---|---|---|
| Humanin | Reduce pro-apoptosis gene expression levels | Nashine et al. (2017) |
| Prevent the loss of AMD mitochondria | ||
| Protect oxidative-stress induced RPE cell death and senescence | Sreekumar et al. (2016) | |
| Prevent oxidative stress-induced decrease in mitochondrial bioenergetics | ||
| Increase mitochondrial DNA copy number | ||
| Upregulate the expression of mitochondrial transcription factor A | ||
| Resveratrol | Improve cell viability | (King et al., 2005; Sheu et al., 2010; Sheu et al., 2013; Nashine et al., 2020; Neal et al., 2020) (Borra et al., 2005) |
| Decrease ROS level | ||
| Stimulate mitochondrial bioenergetics | ||
| Induce autophagy, pro-survival and specific anti-inflammatory response | Josifovska et al. (2020) | |
| Suppress choroidal neovascularization | Nagai et al. (2014) | |
| Activate SIRT1, a key regulator of cellular senescence, aging and longevity | Borra et al. (2005) | |
| Chrysoeriol | Diminish mitochondrial dysfunction | Kim et al. (2021a) |
| Prevent ROS accumulation | ||
| Enhance expression of anti-oxidative genes | ||
| Attenuate oxidative stress-induced mitochondrial membrane potential loss | ||
| Necrostatins | Protect oxidative stress-induced RPE cell death in vitro and in vivo | (Hanus et al., 2015; Hanus et al., 2016) |
| Recover mitochondrial dysfunction and reduce ROS production in response to necroptosis inducer TNFα or acetaminophen | (Ye et al., 2012; Takemoto et al., 2014) | |
| PU-91 | Upregulate PGC-1α | Nashine et al. (2019) |
| Increase mtDNA copy number | ||
| Upregulate the genes involved in mitochondrial biogenesis pathway | ||
| Increase mitochondrial membrane potential | ||
| Decrease the level of mitochondrial superoxide | ||
| Upregulate SOD2 expression level | ||
| TPP-Niacin | Ameliorate H2O2-induced Mitochondrial dysfunction and mitochondrial membrane potential reduction | Kim et al. (2021b) |
| Enhance the expression of transcription factors (PGC-1α and NRF2) and antioxidant-associated genes (HO-1 and NQO-1) | ||
| ZLN005 | Upregulate of PGC-1α and its associated transcription factors, antioxidant enzymes, and mitochondrial genes | Satish et al. (2018) |
| Increase basal and maximal respiration rates, and spare respiratory capacity | ||
| AICAR, Metformin, Trehalose | Maintain RPE mitochondrial function by activating AMPK pathway and boost autophagy | (Zhao et al., 2020) (Ebeling et al., 2022) |
| Rapamycin | Inhibit mTOR and activate autophagy | (Huang et al., 2019; Go et al., 2020) |
| Nicotinamide mononucleotide (NMN) | Improve mitochondrial functions including basal respiration, maximal respiration, spare respiratory capacity and ATP production | Ebeling et al. (2020) |
| Elamipretide | Reduce RPE cell death and senescence. Under phase II clinical trail | Mettu et al. (2022) |
| α-Lipoic acid (LA) | Protect against an acute acrolein-induced RPE cell death | Jia et al. (2007) |
| Prevent mitochondrial membrane potential decrease | ||
| Inhibit generation of intracellular oxidants | ||
| Prevent the intracellular SOD decrease | ||
| Protect mitochondrial complex I, II, and III activity | ||
| Increase intracellular total antioxidant power in RPE cells | ||
| Melatonin | Protect human RPE cells against cytotoxic effects of H2O2 | Rosen et al. (2012) |
| Protect of mtDNA of ARPE-19 cells against H2O2-induced damage | Liang et al. (2004) | |
| SkQ1 | Prevent progression of retinopathy and suppressed atrophic changes in the RPE cells in the senescence-accelerated OXYS rats | (Muraleva et al., 2014; Muraleva et al., 2019; Telegina et al., 2020) |
Abbreviations: RPE, retinal pigmented epithelial; AMD, Age-related macular degeneration; ROS, reactive oxygen species; POS, photoreceptor outer segments; BrM, Bruch’s membrane; IL, interleukin; TNF, tumor necrosis factor; IFN, interferon; TGF, transforming growth factor; TCA, tricarboxylic acid; ER, endoplasmic reticulum; ATP, adenosine triphosphate; mtDNA, mitochondrial DNA; NAD, nicotinamide adenine dinucleotide; GTPase, Guanosine triphosphatases; MFN, mitofusins; Opa1, Optic atrophy 1; Drp1, Dynamin-related protein 1; PGC, Peroxisome proliferator-activated receptor gamma coactivator; NRF, nuclear respiratory factors; TOM, translocase of the outer membrane; Pink1, PTEN-induced putative kinase 1; AMPK, Adenosine5′-monophosphate (AMP)-activated protein kinase; LC3, Microtubule-associated protein 1 light chain 3; TEM, transmission electron microscopy; MT/LT, MitoTracker/LysoTracker; PUFA, polyunsaturated fatty acids; UV, ultraviolet; EMT, Epithelial-mesenchymal transition; GA, geographic atrophy; SD-OCT, spectral domain optical coherence tomography; TUNEL, Terminal deoxynucleotidyl transferase dUTP, nick end labeling; iPSC, induced pluripotent stem cell; NLRP3, NLR, Family Pyrin Domain Containing 3; mtHsp, mitochondrial heat shock protein; CFH, Complement factor H; SIRT1, Sirtuin 1; mTOR, mammalian target of rapamycin; NRF2, Nuclear factor erythroid 2-related factor 2; OXPHOS, oxidative phosphorylation; Fis1, Mitochondrial fission 1 protein; CSE, cigarette smoke extract; PGAM5, Phosphoglycerate mutase 5; H2O2, hydrogen peroxide; ΔΨm, Mitochondrial membrane potential; MOMP, mitochondrial outer membrane permeabilization; BCL-2, B-cell lymphoma 2; BAK, BCL-2, antagonist/killer; BAX, BCL-2–associated X; SMAC, Second mitochondria-derived activator of caspase; MPTP, mitochondrial permeability pore; GSDMD, Gasdermin D; CoQH2, ubiquinol; FSP1, Ferroptosis Suppressor Protein 1; GPX4, Glutathione peroxidase 4; A2E, N-retinylidene-N-retinyl-ethanolamine; tBHP, tert-butyl hydroperoxide; NaIO3, sodium iodate; TXNIP, Thioredoxin-interacting protein; Nec-1, Necrostatin-1; RIPK1, Receptor Interacting Serine/Threonine Kinase 1; PPAR; Peroxisome proliferator-activated receptors; TPP, triphenylphosphonium; AICAR, 5-Aminoimidazole-4-carboxamide ribonucleotide; NMN, nicotinamide mononucleotide; LA, α-Lipoic acid; SkQ1, Plastoquinonyl-decyl-triphenylphosphonium.