Ferrous but not ferric iron sulfate kills photoreceptors and induces photoreceptor-dependent RPE autofluorescence

Shu, Wanting; Baumann, Bailey; Song, Ying; Liu, Yingrui; Wu, Xiang; Dunaief, Joshua L.

doi:10.1016/j.redox.2020.101469

Cited by 48 publications

(42 citation statements)

References 43 publications

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“…Substantial attenuation of LOS accumulation was observed when cells were co-incubated with Fer-1 or DFO. Consistently with recent reports on ferroptosis induction [ 13 , 14 ]. NaIO 3 -induced RPE cell death was also accompanied by ferroptosis-associated characteristics, such as ferrous iron accumulation and lipid peroxidation, which could be significantly attenuated by DFO and Fer-1.…”

Section: Resultssupporting

confidence: 93%

“…, Alzheimer's disease and Parkinson's disease, which is inextricably associated with lipid peroxidation contingent on reactive oxygen species (ROS) levels and the availability of iron [ 12 ]. Recently, RPE ferroptosis induced by GSH depletion, tBH incubation, or direct ferrous iron supplementation was demonstrated as a major pattern of oxidative stress-mediated RPE cell death [ [13] , [14] , [15] ]. Nevertheless, the fundamental mechanisms underlying the pathogenic processes and the cumulative effects of oxidative stress-mediated RPE ferroptosis and subsequent photoreceptor damage are not well elucidated.…”

Section: Introductionmentioning

confidence: 99%

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HO-1-mediated ferroptosis as a target for protection against retinal pigment epithelium degeneration

et al. 2021

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Oxidative stress-mediated retinal pigment epithelium (RPE) degeneration plays a vital role in retinal degeneration with irreversible visual impairment, most notably in age-related macular degeneration (AMD), but a key pathogenic factor and the targeted medical control remain controversial and unclear. In this work, by sophisticated high-throughput sequencing and biochemistry investigations, the major pathologic processes during RPE degeneration in the sodium iodate-induced oxidative stress model has been identified to be heme oxygenase-1 (HO-1)-regulated ferroptosis, which is controlled by the Nrf2–SLC7A11–HO-1 hierarchy, through which ferrous ion accumulation and lethal oxidative stress cause RPE death and subsequently photoreceptor degeneration. By direct knockdown of HO-1 or using HO-1 inhibitor ZnPP, the specific inhibition of HO-1 overexpression has been determined to significantly block RPE ferroptosis. In mice, treatment with ZnPP effectively rescued RPE degeneration and achieved superior therapeutic effects: substantial recovery of the retinal structure and visual function. These findings highlight that targeting HO-1-mediated RPE ferroptosis could serve as an effectively retinal-protective strategy for retinal degenerative diseases prevention, including AMD.

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Section: Resultssupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

HO-1-mediated ferroptosis as a target for protection against retinal pigment epithelium degeneration

et al. 2021

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“…Hepcidin is a peptide hormone secreted mainly by the liver. It maintains systemic iron within a narrow range since iron is essential for vital catalytic reactions, but excess can be highly toxic because of the ease with which it cycles between redox states [ 105 ]. This is achieved by modulating the expression of ferroportin (Fpn), the only known iron export protein.…”

Section: Methodsmentioning

confidence: 99%

Retinal Degeneration and Alzheimer’s Disease: An Evolving Link

Ashok

Singh

Chaudhary

et al. 2020

IJMS

105

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Age-related macular degeneration (AMD) and glaucoma are degenerative conditions of the retina and a significant cause of irreversible blindness in developed countries. Alzheimer’s disease (AD), the most common dementia of the elderly, is often associated with AMD and glaucoma. The cardinal features of AD include extracellular accumulation of amyloid β (Aβ) and intracellular deposits of hyper-phosphorylated tau (p-tau). Neuroinflammation and brain iron dyshomeostasis accompany Aβ and p-tau deposits and, together, lead to progressive neuronal death and dementia. The accumulation of Aβ and iron in drusen, the hallmark of AMD, and Aβ and p-tau in retinal ganglion cells (RGC), the main retinal cell type implicated in glaucoma, and accompanying inflammation suggest overlapping pathology. Visual abnormalities are prominent in AD and are believed to develop before cognitive decline. Some are caused by degeneration of the visual cortex, while others are due to RGC loss or AMD-associated retinal degeneration. Here, we review recent information on Aβ, p-tau, chronic inflammation, and iron dyshomeostasis as common pathogenic mechanisms linking the three degenerative conditions, and iron chelation as a common therapeutic option for these disorders. Additionally discussed is the role of prion protein, infamous for prion disorders, in Aβ-mediated toxicity and, paradoxically, in neuroprotection.

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“…Recently, it has been shown that the deleterious effect of HMOX1 induction may be associated with its catalyzed metabolite ferrous iron, which accelerates mitochondrial iron sequestration [ 15 , 21 ]. Moreover, as HMOX1 is an endoplasmic reticulum (ER)-anchored protein [ 7 ], it is conceivable that it plays a role in ER stress.…”

Section: Introductionmentioning

confidence: 99%

High dose expression of heme oxigenase-1 induces retinal degeneration through ER stress-related DDIT3

Liu

Lian

et al. 2021

Mol Neurodegeneration

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Background Oxidative stress is a common cause of neurodegeneration and plays a central role in retinal degenerative diseases. Heme oxygenase-1 (HMOX1) is a redox-regulated enzyme that is induced in neurodegenerative diseases and acts against oxidative stress but can also promote cell death, a phenomenon that is still unexplained in molecular terms. Here, we test whether HMOX1 has opposing effects during retinal degeneration and investigate the molecular mechanisms behind its pro-apoptotic role. Methods Basal and induced levels of HMOX1 in retinas are examined during light-induced retinal degeneration in mice. Light damage-independent HMOX1 induction at two different expression levels is achieved by intraocular injection of different doses of an adeno-associated virus vector expressing HMOX1. Activation of Müller glial cells, retinal morphology and photoreceptor cell death are examined using hematoxylin-eosin staining, TUNEL assays, immunostaining and retinal function are evaluated with electroretinograms. Downstream gene expression of HMOX1 is analyzed by RNA-seq, qPCR examination and western blotting. The role of one of these genes, the pro-apoptotic DNA damage inducible transcript 3 (Ddit3), is analyzed in a line of knockout mice. Results Light-induced retinal degeneration leads to photoreceptor degeneration and concomitant HMOX1 induction. HMOX1 expression at low levels before light exposure prevents photoreceptor degeneration but expression at high levels directly induces photoreceptor degeneration even without light stress. Photoreceptor degeneration following high level expression of HMOX1 is associated with a mislocalization of rhodopsin in photoreceptors and an increase in the expression of DDIT3. Genetic deletion of Ddit3 in knockout mice prevents photoreceptor cell degeneration normally resulting from high level HMOX1 expression. Conclusion The results reveal that the expression levels determine whether HMOX1 is protective or deleterious in the retina. Furthermore, in contrast to the protective low dose of HMOX1, the deleterious high dose is associated with induction of DDIT3 and endoplasmic reticulum stress as manifested, for instance, in rhodopsin mislocalization. Hence, future applications of HMOX1 or its regulated targets in gene therapy approaches should carefully consider expression levels in order to avoid potentially devastating effects.

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Ferrous but not ferric iron sulfate kills photoreceptors and induces photoreceptor-dependent RPE autofluorescence

Cited by 48 publications

References 43 publications

HO-1-mediated ferroptosis as a target for protection against retinal pigment epithelium degeneration

HO-1-mediated ferroptosis as a target for protection against retinal pigment epithelium degeneration

Retinal Degeneration and Alzheimer’s Disease: An Evolving Link

High dose expression of heme oxigenase-1 induces retinal degeneration through ER stress-related DDIT3

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