bims-mideyd 2024-06-23 papers

Issue of 2024‒06‒23
four papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington

Biosci Rep. 2024 06 26. pii: BSR-2019-4347_EOC. [Epub ahead of print]44(6):

Expression of Concern: Madecassoside protects retinal pigment epithelial cells against hydrogen peroxide induced oxidative stress and apoptosis through the activation of Nrf2/HO-1 pathway.

Keywords: Age‐related macular degeneration (AMD); madecassoside (MADE); oxidative stress; retinal pigment epithelium (RPE)

DOI: https://doi.org/10.1042/BSR-2019-4347_EOC

Mol Neurodegener. 2024 Jun 18. 19(1): 49

Urolithin A promotes p62-dependent lysophagy to prevent acute retinal neurodegeneration.

Juan Ignacio Jiménez-Loygorri, Álvaro Viedma-Poyatos, Raquel Gómez-Sintes, Patricia Boya.

BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of blindness in elderly people in the developed world, and the number of people affected is expected to almost double by 2040. The retina presents one of the highest metabolic demands in our bodies that is partially or fully fulfilled by mitochondria in the neuroretina and retinal pigment epithelium (RPE), respectively. Together with its post-mitotic status and constant photooxidative damage from incoming light, the retina requires a tightly-regulated housekeeping system that involves autophagy. The natural polyphenol Urolithin A (UA) has shown neuroprotective benefits in several models of aging and age-associated disorders, mostly attributed to its ability to induce mitophagy and mitochondrial biogenesis. Sodium iodate (SI) administration recapitulates the late stages of AMD, including geographic atrophy and photoreceptor cell death.METHODS: A combination of in vitro, ex vivo and in vivo models were used to test the neuroprotective potential of UA in the SI model. Functional assays (OCT, ERGs), cellular analysis (flow cytometry, qPCR) and fine confocal microscopy (immunohistochemistry, tandem selective autophagy reporters) helped address this question.
RESULTS: UA alleviated neurodegeneration and preserved visual function in SI-treated mice. Simultaneously, we observed severe proteostasis defects upon SI damage induction, including autophagosome accumulation, that were resolved in animals that received UA. Treatment with UA restored autophagic flux and triggered PINK1/Parkin-dependent mitophagy, as previously reported in the literature. Autophagy blockage caused by SI was caused by severe lysosomal membrane permeabilization. While UA did not induce lysosomal biogenesis, it did restore upcycling of permeabilized lysosomes through lysophagy. Knockdown of the lysophagy adaptor SQSTM1/p62 abrogated viability rescue by UA in SI-treated cells, exacerbated lysosomal defects and inhibited lysophagy.
CONCLUSIONS: Collectively, these data highlight a novel putative application of UA in the treatment of AMD whereby it bypasses lysosomal defects by promoting p62-dependent lysophagy to sustain proteostasis.

Keywords: Age-related macular degeneration; Autophagy; Lysophagy; Lysosomal membrane permeabilization; SQSTM1/p62; Sodium iodate; Urolithin A

DOI: https://doi.org/10.1186/s13024-024-00739-3

J Agric Food Chem. 2024 Jun 19.

Lutein Modulates Cellular Functionalities and Regulates NLRP3 Inflammasome in a H2O2-Challenged Three-Dimensional Retinal Pigment Epithelium Model.

Hang Liu, Chushan Wu, Shiyin Hu, Bin Leng, Xiaowei Lou, Zengping Liu, Xinyi Su, Dejian Huang.

Excessive hydrogen peroxide (H2O2) generated during retinal cell metabolic activity could lead to oxidative degeneration of retinal pigment epithelium (RPE) tissue, a specific pathological process implicated in various retinal diseases resulting in blindness, which can be mitigated by taking dietary antioxidants to prevent inflammation and impaired cellular dysfunction. This study tested the hypothesis that damages induced by oxidative stresses can be mitigated by lutein in a H2O2-challenged model, which was based on an ARPE-19 cell monolayer cultured on three-dimensional (3D)-printed fibrous scaffolds. Pretreating these models with lutein (0.5 μM) for 24 h can significantly lower the oxidative stress and maintain phagocytosis and barrier function. Moreover, lutein can modulate the NLRP3 inflammasome, leading to a ∼40% decrease in the pro-inflammatory cytokine (IL-1β and IL-18) levels. Collectively, this study suggests that the 3D RPE model is an effective tool to examine the capability of lutein to modulate cellular functionalities and regulate NLRP3 inflammation.

Keywords: 3D bioprinting; NLRP3 pathway; lutein; retinal inflammation; retinal pigment epithelium

DOI: https://doi.org/10.1021/acs.jafc.4c01537

Proc Natl Acad Sci U S A. 2024 Jun 18. 121(25): e2402384121

Alternative oxidase blunts pseudohypoxia and photoreceptor degeneration due to RPE mitochondrial dysfunction.

Ming Chen, Yekai Wang, Roopa Dalal, Jianhai Du, Douglas Vollrath.

Loss of mitochondrial electron transport complex (ETC) function in the retinal pigment epithelium (RPE) in vivo results in RPE dedifferentiation and progressive photoreceptor degeneration, and has been implicated in the pathogenesis of age-related macular degeneration. Xenogenic expression of alternative oxidases in mammalian cells and tissues mitigates phenotypes arising from some mitochondrial electron transport defects, but can exacerbate others. We expressed an alternative oxidase from Ciona intestinalis (AOX) in ETC-deficient murine RPE in vivo to assess the retinal consequences of stimulating coenzyme Q oxidation and respiration without ATP generation. RPE-restricted expression of AOX in this context is surprisingly beneficial. This focused intervention mitigates RPE mTORC1 activation, dedifferentiation, hypertrophy, stress marker expression, pseudohypoxia, and aerobic glycolysis. These RPE cell autonomous changes are accompanied by increased glucose delivery to photoreceptors with attendant improvements in photoreceptor structure and function. RPE-restricted AOX expression normalizes accumulated levels of succinate and 2-hydroxyglutarate in ETC-deficient RPE, and counteracts deficiencies in numerous neural retinal metabolites. These features can be attributed to the activation of mitochondrial inner membrane flavoproteins such as succinate dehydrogenase and proline dehydrogenase, and alleviation of inhibition of 2-oxyglutarate-dependent dioxygenases such as prolyl hydroxylases and epigenetic modifiers. Our work underscores the importance to outer retinal health of coenzyme Q oxidation in the RPE and identifies a metabolic network critical for photoreceptor survival in the context of RPE mitochondrial dysfunction.

Keywords: alternative oxidase; coenzyme Q; mitochondrial dysfunction; retinal pigment epithelium; succinate

DOI: https://doi.org/10.1073/pnas.2402384121