Oxidative Stress-Involved Mitophagy of Retinal Pigment Epithelium and Retinal Degenerative Diseases

**Background:** The retinal pigment epithelium (RPE) is a monolayer of cells located between the photoreceptors and the choroid, forming the blood-retina outer barrier. It performs critical functions including nutrient transport, phagocytosis of shed photoreceptor outer segments (POS), and participation in the visual cycle. Due to its high metabolic demands, the RPE contains abundant mitochondria, which also produce reactive oxygen species (ROS) as byproducts. Under physiological conditions, ROS act as second messengers, but excessive ROS from aging, light exposure, smoking, or high-fat diet can cause oxidative stress, damaging lipids, proteins, and DNA. Dysfunctional mitochondria are normally removed via mitophagy, a selective form of autophagy. However, in retinal degenerative diseases such as age-related macular degeneration (AMD) and diabetic retinopathy (DR), mitophagy is impaired, leading to accumulation of damaged mitochondria and triggering apoptosis. This review aims to summarize the signaling pathways of oxidative stress-involved mitophagy in RPE and its role in AMD and DR.

**Methods:** This is a narrative review that synthesizes findings from published studies on mitophagy pathways in RPE cells, including in vitro experiments (e.g., ARPE-19 cells), animal models (e.g., Nrf2 knockout mice, Ins2Akita diabetic mice), and human tissue analyses. The review focuses on three major signaling pathways: PINK1/Parkin-mediated ubiquitin-dependent mitophagy, BNIP3/NIX- and FUNDC1-mediated receptor-dependent mitophagy, and the specific roles of Sirt3/FOXO3a, TXNIP, and Nrf2/p62 in oxidative stress-involved mitophagy in RPE.

**Key Results:** The review highlights that in AMD, excessive ROS production promotes mitophagy in RPE by activating the Nrf2/p62 pathway. For example, Zhao et al. found that Nrf2 knockout in mice led to swollen mitochondria, increased autophagy vacuoles, and features of retinal degeneration such as drusen and lipofuscin accumulation. Felszeghy et al. showed that PGC-1α and Nrf2 double-knockout mice had increased mitophagy-related proteins but impaired mitophagy flux, leading to RPE degeneration and visual dysfunction similar to AMD. In DR, hyperglycemia suppresses mitophagy via the FOXO3a/PINK1–Parkin pathway. Huang et al. reported that under high glucose (HG) conditions, Sirt3 expression in RPE decreased, leading to increased ROS and attenuated FOXO3a/PINK1–Parkin-mediated mitophagy. Overexpression of Sirt3 triggered mitophagy and suppressed apoptosis, but this protection was blocked by PINK1 silencing. Additionally, TXNIP is upregulated under HG conditions, and silencing TXNIP with shRNA reduced ROS and promoted mitophagy in ARPE-19 cells, though excessive mitophagy flux can overwhelm lysosomal capacity. In DR models, Zhang et al. found that HG (50 mM) increased ROS and inhibited PINK1 and Parkin expression, suppressing mitophagy and causing cell death; ROS scavengers or PINK1/Parkin overexpression attenuated damage, while cyclosporin A (a mitophagy inhibitor) exacerbated it. NotoginsenosideR1 (NGR1) treatment in HG-induced retinal Müller cells increased PINK1 and Parkin expression and LC3II/LC3I ratio, and knockdown of PINK1 abolished this protection.

**Clinical Implications:** The review underscores that oxidative stress-induced mitophagy plays a dual role in retinal degenerative diseases. In AMD, promoting mitophagy via Nrf2/p62 may help clear damaged mitochondria and protect RPE. In DR, restoring PINK1/Parkin-mediated mitophagy or modulating TXNIP could mitigate hyperglycemia-induced RPE damage. Current therapies for AMD and DR primarily target anti-neovascularization with anti-VEGF drugs, but results are often unsatisfactory. Directly or indirectly regulating mitophagy may offer a novel therapeutic strategy. However, challenges remain: multiple mitophagy pathways interact, and specific drugs are lacking. Future research should focus on deciphering exact molecular mechanisms, identifying key targets, and developing efficient regulators of mitophagy to treat retinal degenerative diseases.