PU-91 drug rescues human age-related macular degeneration RPE cells; implications for AMD therapeutics

Abstract

Since mitochondrial dysfunction is implicated in the pathogenesis of AMD, this study is based on the premise that repurposing of mitochondria-stabilizing FDA-approved drugs such as PU-91, might rescue AMD RPE cells from AMD mitochondria-induced damage. The PU-91 drug upregulates PGC-1α which is a critical regulator of mitochondrial biogenesis. Herein, we tested the therapeutic potential of PU-91 drug and examined the additive effects of treatment with PU-91 and esterase inhibitors i.e., EI-12 and EI-78, using the in vitro transmitochondrial AMD cell model. This model was created by fusing platelets obtained from AMD patients with Rho0 i.e., mitochondria-deficient, ARPE-19 cell lines. The resulting AMD RPE cell lines have identical nuclei but differ in their mitochondrial DNA content, which is derived from individual AMD patients. Briefly, we report significant improvement in cell survival, mitochondrial health, and antioxidant potential in PU-91-treated AMD RPE cells compared to their untreated counterparts. In conclusion, this study identifies PU 91 as a therapeutic candidate drug for AMD and repurposing of PU-91 will be a smoother transition from lab bench to clinic since the pharmacological profiles of PU-91 have been examined already.

Role of Resveratrol in Transmitochondrial AMD RPE Cells

“…All AMD patients used in this study have been clinically characterized, and genetic and clinical information of all patients is available as partly mentioned in Table 1. Morphological and functional evaluation of these AMD RPE transmitochondrial cell lines in our previous studies revealed significant mitochondrial and cellular damage as evidenced by apoptotic cell death, higher oxidative stress, low antioxidant content, lower numbers of mitochondria, and higher mtDNA fragmentation in AMD RPE cells [9][10][11][12][13]. Therefore, AMD RPE transmitochondrial cell lines serve as a good in vitro model to test the effects of resveratrol as a potential over-the-counter candidate for AMD therapy.…”

Recent Advances in Our Understanding of Age-Related Macular Degeneration: Mitochondrial Dysfunction, Redox Signaling, and the Complement System

“…Given the anti-inflammatory, antioxidant, and proautophagic activities of zinc, dietary supplementation may be hypothesized as a valuable tool in AMD prevention. Dedicated studies have reported that zinc supplementation in combination with the AREDS formula has the potential to slow AMD progression, while a higher intake of dietary zinc has beneficial effects on AMD incidence [450][451][452][453] [454]. The same research group expanded their investigation, revealing varied responses to PU-91 drug treatment among AMD cybrids with different mtDNA haplogroups [455].…”

Potential application of traditional Chinese medicine in age-related macular degeneration—focusing on mitophagy

“…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 (5aminoimidazole-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.…”