bims-mideyd 2022-12-18 papers

Issue of 2022‒12‒18
four papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington

Free Radic Biol Med. 2022 Dec 09. pii: S0891-5849(22)01034-6. [Epub ahead of print]194 245-254

Induction of ferroptosis by HO-1 contributes to retinal degeneration in mice with defective clearance of all-trans-retinal.

Chao Chen, Kunhuan Yang, Danxue He, Bo Yang, Lei Tao, Jingmeng Chen, Yalin Wu.

The accumulation of all-trans-retinal (atRAL) in photoreceptors and the retinal pigment epithelium (RPE), which is induced by chaos in visual (retinoid) cycle, is closely associated with the pathogenesis of dry age-related macular degeneration (AMD) and autosomal recessive Stargardt's disease (STGD1). Although we have reported that the induction of ferroptosis by atRAL is an important cause of photoreceptor loss, but its mechanisms still remain unclear. In this study, we identified heme oxygenase-1 (HO-1) as an inducer of photoreceptor ferroptosis elicited by atRAL. In atRAL-loaded photoreceptor cells, inhibition of Kelch-like ECH-associated protein 1 (KEAP1) at least in part by reactive oxygen species (ROS) production evoked the release of nuclear factor-erythroid 2-related factor-2 (NRF2) from KEAP1, followed by the translocation of active NRF2 into the nucleus where it promoted the transcription of the Ho-1 gene, thereby leading to HO-1 overexpression in the cytosol. A significant elevation of Fe2+ levels in photoreceptor cells resulted from activation of HO-1 by atRAL, and it facilitated ROS overproduction and then triggered ferroptotic cell death through ROS-mediated lipid peroxidation. Both treatment with HO-1 repressor Zinc protoporphyrin IX (ZnPP) and knockout of Ho-1 gene clearly rescued photoreceptor cells against ferroptosis arising from atRAL overload. Light-exposed Abca4-/-Rdh8-/- mice rapidly display severe defects in atRAL clearance, and serve as an acute model of dry AMD and STGD1. HO-1 activation was distinctly observed in neural retina of Abca4-/-Rdh8-/- mice after exposure to light, and it was visibly relieved by intraperitoneally injected ferroptosis inhibitor ferrostatin-1. More notably, intraperitoneal administration of ZnPP effectively alleviated both photoreceptor degeneration and RPE atrophy in Abca4-/-Rdh8-/- mice in response to light exposure by repressing HO-1-mediated ferroptosis. Our study suggests that HO-1 is a key factor that regulates atRAL-induced ferroptosis in photoreceptors and the RPE, and its inhibition may hold promises for the therapy of dry AMD and STGD1.

Keywords: Ferroptosis; Heme oxygenase-1; Macular degeneration; Photoreceptor; Retinal pigment epithelium; Stargardt's disease

DOI: https://doi.org/10.1016/j.freeradbiomed.2022.12.008

Sci Rep. 2022 Dec 16. 12(1): 21725

Investigating mitochondrial fission, fusion, and autophagy in retinal pigment epithelium from donors with age-related macular degeneration.

Cody R Fisher, Adam A Shaaeli, Mara C Ebeling, Sandra R Montezuma, Deborah A Ferrington.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in developed countries, characterized by the death of retinal pigment epithelial (RPE) cells and photoreceptors. Previous studies report an accumulation of damaged and dysfunctional mitochondria in RPE of human donors with AMD. Understanding how damaged mitochondria accumulate in AMD is an important step in discovering disease mechanisms and identifying therapeutic targets. In this report, we assessed mitochondrial fission and fusion by quantifying proteins and measured mitochondrial autophagy (mitophagy) via protein analysis and advanced imaging techniques using mitochondrial targeted mKeima in primary human RPE from donors with or without AMD. We report disease-specific differences in mitochondrial proteins that regulate fission, fusion, and mitophagy that were present at baseline and with treatments to stimulate these pathways. Data suggest AMD RPE utilize receptor-mediated mitophagy as a compensatory mechanism for deficits in the ubiquitin-mediated mitophagy pathway. These changes in mitochondrial homeostasis could lead to the buildup of damaged and dysfunctional mitochondria observed in the RPE of AMD donors.

DOI: https://doi.org/10.1038/s41598-022-26012-5

Int J Mol Sci. 2022 Nov 25. pii: 14771. [Epub ahead of print]23(23):

New Insights into Dose-Dependent Effects of Curcumin on ARPE-19 Cells.

Giulia Carozza, Annamaria Tisi, Annamaria Capozzo, Benedetta Cinque, Aldo Giovannelli, Marco Feligioni, Vincenzo Flati, Rita Maccarone.

Opposing dose-dependent effects of curcumin (Cur) have been documented in Retinal Pigment Epithelium (RPE); therefore, to shed the light on the mechanisms of action is crucial for ophthalmic applications. On this basis we explored new insights about the dose-dependent mechanisms triggered by Cur in human retinal pigment epithelial cells (ARPE-19). Three concentrations (0.01 mM; 0.05 mM; 0.1 mM) of Cur were tested, followed by morphological, molecular, and functional analysis of the cells. Cur 0.01 mM promotes a significant increase in cell proliferation, not affecting cell cycle progression and apoptosis; by contrast, Cur 0.05 mM and 0.1 mM block cellular proliferation and trigger S-phase cell cycle arrest without inducing apoptosis. The observation of neuronal-like morphological changes in Cur 0.05 mM and 0.1 mM were not associated with neuronal differentiation, as observed by the quantification of Neurofilament-200 and by the analysis of voltage-dependent currents by patch clamp. Evaluation of autophagic markers LC3BII and p62 revealed significant modulations, suggesting an important activation of autophagy in ARPE-19 cells treated with Cur 0.05 mM and Cur 0.1 mM; conversely, Cur 0.01 mM did not affect autophagy. Altogether, our findings show new dose-dependent mechanisms of action of Cur that suggest a wide therapeutic application in ocular diseases with different pathogenesis (i.e., proliferative vitreoretinopathy or Age-Related Macular Degeneration).

Keywords: ARPE-19; LC3BII; autophagy; cell cycle; curcumin; p62; retinal pigment epithelium

DOI: https://doi.org/10.3390/ijms232314771

Cell Death Discov. 2022 Dec 12. 8(1): 489

UVA induces retinal photoreceptor cell death via receptor interacting protein 3 kinase mediated necroptosis.

Zhen Yu, Victor S M C Correa, Nikolaos E Efstathiou, Henar Albertos-Arranz, Xiaohong Chen, Kenji Ishihara, Yasuhiro Iesato, Toshio Narimatsu, Dimitrios Ntentakis, Demetrios G Vavvas.

Ultraviolet light A (UVA) is the only UV light that reaches the retina and can cause indirect damage to DNA via absorption of photons by non-DNA chromophores. Previous studies demonstrate that UVA generates reactive oxygen species (ROS) and leads to programmed cell death. Programmed cell death (PCD) has been implicated in numerous ophthalmologic diseases. Here, we investigated receptor interacting protein 1 and 3 (RIPK1 and RIPK3) kinases, key signaling molecules of PCD, in UVA-induced photoreceptor injury using in vitro and ex vivo models. UVA irradiation activated RIPK3 but not RIPK1 and mediated necroptosis through MLKL that lie downstream of RIPK3 and induced apoptosis through increased oxidative stress. Moreover, RIPK3 but not RIPK1 inhibition suppresses UVA-induced cell death along with the downregulation of MLKL and attenuates the levels of oxidative stress and DNA fragmentation. In conclusion, these results identify RIPK3, not RIPK1, as a critical regulator of UVA-induced necroptosis cell death in photoreceptors and highlight RIPK3 potential as a neuroprotective target.

DOI: https://doi.org/10.1038/s41420-022-01273-1