Autophagy is a multifunctional degradation system that helps cells maintain homeostasis by encapsulating cytoplasmic proteins, damaged organelles, and pathogens into vesicles (autophagosomes), which subsequently fuse with lysosomes to create autolysosomes, leading to the degradation of the encapsulated cargo and the generation of amino acids, nucleotides, sugars, fatty acids, and adenosine triphosphate (ATP). By assisting in the regulation of protein, nucleic acid, and lipid balances, the modulation of reactive oxidative stress and oxygen species (ROS), and the improvement of mitochondrial function, autophagy contributes to cellular metabolic needs and the renewal of intracellular organelles (Nita and Grzybowski, 2023). Depending on the intracellular lysosomal degradation mechanism, three distinct forms of autophagy—macroautophagy, microautophagy, and chaperone-mediated autophagy—have been distinguished (Mizushima, 2018; Yao and Shen, 2020) (Figure 1). Macroautophagy is the most predominant and conserved type of autophagy and proceeds via five stages—induction, nucleation, extension, fusion, and degradation (Nieto-Torres and Hansen, 2021). During chaperone-mediated autophagy, the chaperone Hsc70 and co-chaperones identify target proteins containing KFERQ-like motifs and then transport these proteins to the lysosomal membrane to bind to the lysosomal receptor lysosomal-associated membrane protein 2A (LAMP2A), triggering receptor multimerization, cargo internalization, and degradation (Gómez-Sintes and Arias, 2021). In contrast, during microautophagy, the target proteins are directly engulfed by the lysosomal membrane through invagination (Fleming et al., 2022).

Mitophagy, a highly specialized type of autophagy, regulates mitochondrial fission and fusion, thereby eliminating malfunctioning and impaired mitochondria, promoting mitochondrial renewal, preventing ROS overproduction, inhibiting potential cellular oxidative damage, and ensuring mitochondrial quality (Wen et al., 2023). In response to ROS generation, nutrient deficiency, cellular senescence, and other factors, intracellular mitochondria are damaged and depolarized. During mitophagy, the impaired mitochondria are incorporated into autophagosomes, which then fuse with lysosomes, resulting in the breakdown of these organelles (Lu et al., 2023). Mitophagy is also involved in numerous physiological functions, such as delaying the ageing process and cell differentiation. Interference in these processes induces physiological senescence and several age-related diseases (Krantz et al., 2021; Banarase et al., 2023; Sanz et al., 2023). Recent evidence indicates that impaired mitochondrial energy metabolism and age-related diseases share pathological features, such as an increased mutation rate in mitochondrial DNA (mtDNA), impaired electron transport chain function, elevated ROS levels, and the enhanced release of pro-apoptotic factors (Fang et al., 2017). As a result, the dysregulation of mitophagy can induce mitochondrial dysfunction, leading to the progression of age-related diseases.

Age-related macular degeneration (AMD) is a lesion on the macula that primarily affects the retinal pigment epithelium (RPE), photoreceptor cells, Bruch’s membrane, and choroidal multilayered tissue. Gradual degeneration of the outer retina and the formation of new blood vessels between the retina and Bruch’s membrane can advance to geographic atrophic or choroidal neovascular AMD, commonly known as dry and wet AMD, respectively (Figure 2). It is estimated that the worldwide occurrence of AMD stands at 196 million, with projections suggesting an increase to 288 million by 2040 (Xiao et al., 2023). RPE cells are known for high oxygen consumption, continuous photostimulation, and susceptibility to lipid peroxidation product exposure (Kaarniranta et al., 2009). Consequently, oxidative stress and damage play a crucial role in the progression of RPE degeneration in AMD (Handa, 2012; Blasiak et al., 2013). Persistent oxidative stress on RPE cells may result in the accumulation of extracellular deposits and damaged organelles, nucleic acids, lipids, cellular proteins, and lipofuscin granules, thereby increasing the levels of ROS. These excessive levels of oxidized lipoproteins and ROS induce protein misfolding, aggregation, and persistent activation of the innate immune responses, leading to protein accumulation, mitochondrial dysfunction, and inflammasome activation in the RPE cells (Ferrington et al., 2016; Kauppinen et al., 2016; Piippo et al., 2018; Kaarniranta et al., 2019a; Kaarniranta et al., 2020). Mitochondria are the important sites of retinal oxidation and are mainly found within the RPE. Mitochondrial dysfunction reduces oxidative phosphorylation, results in excessive ROS production, increases mtDNA damage and mutations, and enhances the release of pro-inflammatory and pro-apoptotic factors, which induce oxidative stress, inflammatory response, and apoptosis (Murphy, 2009; Kageyama et al., 2012; Kaarniranta et al., 2020). Studies have shown that mitophagy regulates RPE cell damage and apoptosis by maintaining mitochondrial function and protein folding (Dhirachaikulpanich et al., 2022; Hyttinen et al., 2023).

Meanwhile, excessive accumulation of extracellular deposits inhibits mitophagy and promotes inflammation in AMD, whereas reduced accumulation restores mitophagy in RPE cells, alleviating AMD (Yu et al., 2023). Damage to mtDNA might be crucial in advancing AMD (Kaarniranta et al., 2019b). Recent reports have indicated that mtDNA damage increases with age; furthermore, elevated mtDNA damage, a higher number of mutations, and reduced DNA repair efficacy have been reported to be associated with the onset and staging of AMD (Piippo et al., 2018). Feher et al. (2006) reported a notable decline in the number of mitochondria and the absence of stromal density and cristae in the RPE of individuals with AMD compared to those in the control group. Zhao et al. (2011) stated that the suppression of oxidative phosphorylation in mouse RPE mitochondria led to the activation of the mechanistic target of the rapamycin (mTOR) pathway in an AMD mouse model. Proteomic analyses performed by Nordgaard et al. (2006) showed the differential expression of mitochondrial refolding and trafficking-related proteins in the RPE of AMD patients compared to that in the non-AMD controls. Subsequent research (Nordgaard et al., 2008) demonstrated that depending on the stage of AMD, the expression of mtHsp70, the mitochondrial translation factor Tu, mitofilin, subunit VIb of the cytochrome c oxidase complex, and α-, β-, and δ-subunits of the catalytic portion of ATP synthase was affected in the RPE. Using an in vitro model of AMD generated by fusing mitochondria-rich platelets from patients with AMD and mitochondrially-depleted retinal pigment epithelial cells (ARPE-19), Dohl et al. (2022) reported increased concentrations of ROS, which could result in mtDNA damage, enhanced antioxidant responses, and increased expression levels of anti-inflammatory proteins. These results suggested that mtDNA damage response was fundamental in preventing AMD and slowing its progression. New findings indicate that boosting autophagy in RPE cells could be an innovative approach to tackle AMD.

Nevertheless, there are few approved mitophagy-modulating medications for AMD treatment. Current clinical AMD therapy includes lifestyle improvements (e.g., caloric restriction and moderate exercise) as well as pharmacological treatments [e.g., antioxidants (D Aloisio et al., 2022), tyrosine kinase inhibitors (Das et al., 2023), antidiabetic drugs (Thee et al., 2021; Mauschitz et al., 2022), anti-vascular endothelial growth factor (anti-VEGF), and other therapies (Francisco and Rowan, 2023; Servillo et al., 2023; Szigiato et al., 2023)]. Lately, traditional Chinese medicine (TCM) has garnered increasing attention for its antioxidant, anti-apoptotic, anti-inflammatory, and lipid-reducing activities, positioning it as a promising treatment option for AMD (Cao et al., 2022a; Yu et al., 2024). This review focuses on the molecular mechanisms governing mitophagy and innovative treatment approaches for employing TCM as a potential AMD therapy.

As summarized in the previous section, mitophagy is strongly associated with the pathogenesis of AMD. Therefore, drugs that activate mitophagy in RPE cells could provide a novel therapeutic strategy for AMD. Recently, numerous mitophagy modulators that either activate or inhibit mitophagy, including AICAR (5-aminoimidazole-4-carboxamide ribonucleotide), an AMP analogue that maintains the optimal function of mitochondria (Ebeling et al., 2022), PGC-1α (an important regulator of mitochondrial biosynthesis) (Hyttinen et al., 2021), human retinal progenitor cells (hRPCs) (Yu et al., 2021), the mitochondria-targeted antioxidant triphenylphosphine (TPP)-nicotinic acid (Kim et al., 2021), melatonin (Mehrzadi et al., 2020), the mitochondrial activator PU-91 (Nashine et al., 2019), the mitochondria-derived peptide variant Humanin G (HNG) (Nashine et al., 2017), and the mitochondria-targeted antioxidant SkQ1 (Telegina et al., 2020; Fisher et al., 2022), have been discovered. mtDNA repair could be another target for improving mitochondrial function. Poly (ADP-ribose) polymerase (PARP1) active base excision repair (BER) and microhomology-mediated end-joining (MMEJ), among others, restore single- and double-strand breaks in mtDNA. Similar to nuclear DNA, nucleic acid complexes of multiple proteins can protect mtDNA from histone binding-induced ROS damage. However, owing to the complexity of mtDNA, its repair needs to be further investigated (Kaarniranta et al., 2020). Furthermore, these studies are still limited to animal and preclinical experiments, and the potential side effects during AMD treatment must be evaluated. A recent study demonstrated that augmenting mitophagic activity in individuals with AMD can impede the progression of the disease (Amini et al., 2023). The complexity of AMD pathogenesis should not be overlooked, as it encompasses a multitude of signaling crosstalks connecting the various layers of retinal structures to the choroid; as a result, positive outcomes are often difficult to achieve using single-agent therapy.

TCM treats diseases through various active ingredients, which possess antioxidant, anti-ageing, immunomodulatory, and anti-inflammatory properties as well as the ability to regulate mitophagy, and could thus be considered as an alternative therapeutic strategy for AMD. In China, Astragalus mongholicus Bunge, Poria cocos (Schw.) Wolf, Plantago asiatica L., Atractylodes macrocephala Koidz., Angelica sinensis (Oliv.) Diels, Panax ginseng C.A.Mey., Salvia miltiorrhiza Bunge, Curcuma longa L. (Pfahler et al., 2022; Vallée, 2022), Rehmannia glutinosa (Gaertn.) DC., Lycium chinense Mill., and Glycyrrhiza glabra L. (Kozlowski et al., 2015; Lee et al., 2015; Peng et al., 2016; Chen et al., 2021; Li et al., 2022a; Cho et al., 2023; Wei and Tong, 2023) are commonly used for the treatment of AMD. Studies have demonstrated that Fructus lycii can selectively activate and regulate the AMPK and VEGF pathways to enhance mitophagy, thereby preventing the development of retinopathy (Yang et al., 2022c). Another TCM, Mingmu Di Huang Pill, treats AMD by activating the expression of autophagy adaptor-SQSTM1 and AMPK phosphorylation, which can promote the autophagic degradation of Kelch-like ECH-related protein 1 (Keap1), safeguarding RPE cells against oxidative stress damage (Chen et al., 2022) (the main active ingredients, pharmacological actions, and mechanisms of these Chinese medicines are summarized in Table 1). Furthermore, various natural products from TCM, including berberine (BBR), curcumin, artemisinin, paeoniflorin, quercetin, luteolin, naringenin, ivytin (Cao et al., 2022b), urinary apolipid A (UA), ferulic acid, and astaxanthin (Lewis Luján et al., 2022), have been reported to have a mitophagy-regulating effect in numerous diseases by activating several specific pathways, including AMPK, PINK1/Parkin, BNIP3, FUNDC1, as well as LC3 proteins, followed by the induction of autolysosome formation. For example, UA, a novel mitophagy enhancer, initiates mitophagy by decreasing MMP without disrupting the mitochondrial respiratory chain and ROS production. Furthermore, it activates mitophagy by inducing the proper mitochondria function in a dose-dependent manner (Lu et al., 2023) and improves immune function through the PINK1/Parkin-mediated pathway (Denk et al., 2022). A previous study proposed that BBR has anti-inflammatory, antioxidant, antimicrobial, hypotensive, and gastric mucosa protective properties (Wang et al., 2017) as well as the ability to prevent oxidative damage triggered by hydrogen peroxide in human RPE cell line D407 via the activation of AMPK, indicating the potential therapeutic application of BBR for AMD (Li et al., 2018). Wang et al. (2023b) also demonstrated that BBR could act as a potential inducer of mitophagy, inhibiting PINK1 promoter methylation, reversing D-ribose-induced mitochondrial dysfunction, and restoring mitophagy via the PINK1/Parkin pathway, thereby attenuating the ageing process. Lu et al. (2023) reported that curcumin, a diketone extracted from the rhizomes of plants in the Zingiberaceae and Araceae, could potentially enhance Parkin-dependent mitophagy through the AMPK/transcription factor EB (TFEB) signaling pathway to diminish oxidative stress-induced injury to the intestinal barrier and mitochondrial dysfunction (Zhang et al., 2023). By activating AMPK, paeoniflorin, a monoterpene glycoside derived from Paeonia lactiflora, mitigates oxidative stress associated with Nox1/ROS in RPE cells, mitochondrial damage, and endoplasmic reticulum stress while protecting ARPE-19 cells and arresting the advancement of retinal degenerative disorders like AMD (Zhu et al., 2018) (Table 2). The latest evidence suggests that TCM or its active components could regulate mitophagy-related proteins, presenting a promising approach to treating AMD.

Mitophagy is an important mitochondrial quality control mechanism that selectively eliminates dysfunctional mitochondria to maintain cellular homeostasis. The regulation of mitophagy is mediated mainly by PINK1/Parkin, BNIP3/NIX, FUNDC1, and AMPK, and its dysfunction is closely related to AMD development. The use of drugs to increase mitophagy in RPE cells provides new ideas for AMD treatment.

Exploration of the relationship between TCM and mitophagy could offer key insights. The findings of such studies could broaden the scope of research on TCM theories by providing insights into how TCM can prevent and control AMD. In recent years, very few reports on TCM treatment of AMD by modulating mitophagy-related pathways have been published. In the present review, the authors focused on the role of mitophagy-related pathways in AMD pathogenesis, drawing on previous studies. In addition, the authors demonstrated potential ways via which TCM could modulate mitophagy to improve AMD based on three aspects: single botanical drugs, botanical drug decoction, and natural chemical components of TCM. However, although multiple pathways can mediate mitophagy, the correlation between the mediating pathways and the exact mechanism of mitophagy-induced AMD has not been elucidated. In future, more animal experiments and clinical experiments should be conducted under various pathological mechanisms to explore the role of mitophagy in AMD. In addition, studies on the regulation of mitophagy by TCM considering specific pharmacodynamics, target pathway, and mechanism of action should be carried out, to clarify the pathways through which the different active ingredients in single botanical drugs regulate mitophagy, and the mitophagy pathways via which different dosages and combinations of TCM could influence the overall AMD regulation, with a view to provide novel clinical insights and methods for the treatment of AMD with TCM.