Melatonin inhibits NaIO3-induced ARPE-19 cell apoptosis via suppression of HIF-1α/BNIP3-LC3B/mitophagy signaling

Abstract

Background Age-related macular degeneration (AMD) leads to gradual central vision loss and eventual irreversible blindness. Melatonin, an endogenous hormone, exhibits anti-inflammatory and antitumor effects; however, the role it plays in AMD remains unclear. Herein, we investigated the anti-AMD molecular mechanism of melatonin after sodium iodate (NaIO3) treatment of ARPE-19 cells in vitro and in animal models with the goal of improving the therapeutic effect. Results The in vitro results showed that melatonin protected against NaIO3-induced cell viability decline, mitochondrial dysfunction and apoptosis in ARPE-19 cells, and melatonin also alleviated NaIO3-induced reactive oxygen species (ROS) production, mitochondrial dysfunction and mitophagy activation. Melatonin reduced NaIO3-induced mitophagy activation through HIF-1α-targeted BNIP3/LC3B transcription, whereas ROS inhibition realized with N-acetylcysteine (NAC, a ROS inhibitor) combined with melatonin reduced the effect of NaIO3 on mitophagy. An animal model of AMD was established to confirm the in vitro data. Mouse tail vein injection of NaIO3 and melatonin was associated with enhanced repair of retinal layers within 7 days, as observed by optical coherence tomography (OCT) and hematoxylin and eosin (H&E) staining. A reduction in BNIP3 and HIF-1α levels, as determined by immunohistochemistry (IHC) assay, was also observed. Conclusions These results indicate that melatonin attenuated NaIO3-induced mitophagy of ARPE-19 cells via reduction in ROS-mediated HIF-1α targeted BNIP3/LC3B signaling in vitro and in vivo. Melatonin may be a potential therapeutic drug in the treatment of AMD.

Inhibition of VHL by VH298 Accelerates Pexophagy by Activation of HIF-1α in HeLa Cells

“…Various studies have shown that HIF-1α upregulates the expression of the mitophagy receptor protein BNIP3L/NIX to promote mitochondrial clearance under hypoxic conditions in several cancer cell lines [ 39 , 40 , 41 , 42 ]. BNIP3L-dependent mitophagy leads to a metabolic shift toward glycolysis [ 40 ].…”

The protective effects of beta-mangostin against sodium iodate-induced retinal ROS-mediated apoptosis through MEK/ERK and p53 signaling pathways

“…• Group II (NaIO 3 only): PBS (pretreatment; IP delivery) + NaIO 3 (40 mg kg −1 ; IV delivery). 3,23…”

“…• Group II (NaIO 3 only): PBS ( pretreatment; IP delivery) + NaIO 3 (40 mg kg −1 ; IV delivery). 3,23 • Group III (BM + NaIO 3 ): BM (20 mg kg −1 ; pretreatment; IP delivery) + NaIO 3 (40 mg kg −1 ; IV delivery). 3…”

Choroidal Mast Cells and Pathophysiology of Age-Related Macular Degeneration

“…Although NaIO 3 is not directly involved in AMD pathology, it provides a means to understand the mechanisms of RPE cell death and likely choriocapillaris degeneration as key pathogenic markers of AMD [ 48 ]. Recent studies have shown that NaIO 3 induces oxidative damage and promotes apoptosis in RPE cells [ 59 , 60 ], characterized by decreased cell viability, increased ROS levels, increased expression of pro-apoptotic proteins such as Bax and cleaved caspase-3 [ 61 , 62 , 63 , 64 ], and decreased Bcl-2 expression [ 62 ]. Interestingly, a peptide derived from a highly conserved region of the human lens protein αA-crystallin, known as mini-αA, has a protective effect against NaIO 3 -induced outer retinal degeneration [ 65 , 66 ].…”