Table 2.

The effects of natural products on mitochondrial quality control (MQC) and/or cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway in age-related macular degeneration (AMD) models.

Agent	Mechanism	Cell types affected or animal models	Administration	Findings	Refs.
Resveratrol	Alu-RNA↓ cGAS↓	Alu-RNA transfected RPE-19 cells	40 μM pretreated	Alu-RNA induced RPE death↓cGAS-induced immune responses↓	[86]
Urolithin A	mTOR↓ PINK1/Parkin pathway↑ Mitochondrial biogenesis↑	Old mice	2.3 mg/kg/day (i.p.) for 8 weeks	Scotopic vision and quality↑ Expression of retinol metabolism genes↑ Glial activation in the retina of old mice↓	[89]
EGCG	Alu-RNA↓ cGAS↓	Alu-RNA transfected RPE-19 cells	20, 40 μM pretreated	Alu-RNA induced RPE death↓ cGAS-induced immune responses↓	[86]
	Formation of LC3-II↓ Autophagosomes↓	UV-B exposure RPE-19 cells	50 μM for 3 h	Toxic effects of UV-B↓	[121]
Crocetin	mTORC1↓ VEGF, IL-1β, and HIF-1α↓	Endothelial cells	100, 200 μM	Rate of proliferating cells↓ Cell migration↓ Tube formation↓	[125]
		Cobalt chloride-induced RPE-19 cells	50, 100 μM	Hypoxic injury↓
		Laser-induced CNV mouse model	100 mM/1 μL/eye IVI	Laser-induced CNV↓
Curcumin	LC3-II/LC3-I ratio↑	Autophagy inhibitor-treated RPE cells from human	10 μM	Autophagy↑	[128]
HHC	Bcl-2↑, Bax↓ SOD2, Beclin-1, p62 and LC3-II↑	Blue light exposure RPE-19 cells Primary RPE cells from blue light exposure mouse	1, 5 and 15 μM	Autophagic flux↑ Oxidative stress↓ Endoplasmic reticulum stress↓	[130]
Quercetin	SOD2↓ Catalase, GSH, diacetyl-SOD2↑ LC3↓	NaIO3-treated mouse model	100 mg/kg (i.p.)	ROS production↓ Drusen-like uneven lesions↓ Ameliorated the deformation of the retinal layers Pupillary response↓	[134]
	p-Nrf2, HO-1, Sirt1, and PGC-1α↓ Beclin-1, LC3B-II, and p62↓ Bcl-2↑	NaIO3-treated RPE-19 cells	1.25, 2.5 and 5 μM pretreated	ROS production↓ Autophagy and mitochondrial biogenesis↓
Lycium barbarum L. berry extracts (scopoletin, perlolyrine, and N-trans-feruloyltyramine)	SOD, GSH↑ IL-6, IL-1β and TNF-α↓	1% hydroquinone diet fed AMD mice model	Water extract: 1105 mg/kg/day for 3 months	Retinal degeneration↓ ROS production↓ Pro-inflammation cytokines↓ Altered serum metabolite	[136]
			Ethanol extract: 173 mg/kg/day for 3 months
	SOD, GSH↑ Nrf2↑ the heme HO-1↑	Sodium iodate-treated RPE cell	LBW-95E: 1, 3 and 10 μg/mL	Cell viability↑ Antioxidant capacity↑
LBP	Nrf2↑	Light-induced AMD mice model	150 or 300 mg/kg	Retinal damage caused by exposure to light↓ ROS production↓ Antioxidative genes↑ Oxidative stress↓	[138]
Berberine	Preserve ΔΨm; Caspase 3/7↓ Phosphorylation of AMPK↑	H2O2-treated D407 cells	0.3, 1 and 3 μM	ROS production↓ Cell death and apoptosis↓ Abnormal changes in nuclear morphology↓	[142]
		H2O2-treated hRPE cells
	Caspase 3/7↓ LC3-BII/LC3-BI↑, autophagy↑ Phosphorylation of AMPK and ULK1↑ mTORC1↓	H2O2-treated D407 cells	1, 3 and 6 μM	Cell death and apoptosis↓	[144]
		H2O2-treated hRPE cells
Luteolin	Nrf2 nuclear translocation↑ HO-1, SOD and GSH↑ p-AKT, GSK-3β↓	H2O2-treated RPE-19 cells	10, 20 and 40 mM	Cell death and apoptosis↓ Cell migration↓ H2O2-induced EMT↓	[150]

The “↑” arrow means upregulation, and the “↓” arrow means downregulation.

RPE: retinal pigment epithelium; mTOR: mammalian target of rapamycin; PINK1: PTEN-induced putative kinase1; EGCG: epigallocatechin gallate; LC3: microtubule-associated protein 1 light chain 3; UV-B: ultraviolet b; mTORC1: rapamycin complex 1; VEGF: vascular endothelial growth factor; IL-1β; interleukin 1-beta; HIF-1α: hypoxia-inducible factor 1-alpha; CNV: choroidal neovascularization; IVI: intravitreal injection; HHC: hexahydrocurcumin; Bcl-2: B-cell lymphoma-2; BAX: Bcl-2-associated X protein; SOD2: superoxide dismutase 2; p62: sequestosome-1; GSH: glutathione; ROS: reactive oxygen species; Nrf2: nuclear factor erythroid 2-related factor 2; HO-1: heme oxygenase-1; Sirt1: silent information regulator 1; TNF-α: tumor necrosis factor-α; LBW-95E: water extracts of L. barbarum berries eluted with 95% ethanol; LBP: Lycium barbarum polysaccharides; ΔΨm: mitochondrial membrane potential; AMPK: adenosine monophosphate-activated protein kinase; ULK1: UNC-51-like kinase 1; hRPE: human retinal pigment epithelial; AKT: protein kinase B; GSK-3: glycogen synthase kinase-3; EMT: epithelial-mesenchymal transition.