Differential participation of phospholipase A2 isoforms during iron-induced retinal toxicity. Implications for age-related macular degeneration

Diez, Guadalupe Rodríguez; Uranga, Romina María; Mateos, Melina Valeria; Giusto, Norma M.; Salvador, Gabriela Alejandra

doi:10.1016/j.neuint.2012.06.012

Cited by 12 publications

(14 citation statements)

References 53 publications

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“…Our laboratory has previously characterized the effects of Fe-induced oxidative stress on cerebral cortex synaptic endings, retina and hippocampal neurons [21,22,25]. We have also described the activation of several signaling pathways related to lipid messengers during metal induced oxidative injury in the above-mentioned experimental models [19–21,26,27].…”

Section: Resultsmentioning

confidence: 99%

Dopaminergic Neurons Respond to Iron-Induced Oxidative Stress by Modulating Lipid Acylation and Deacylation Cycles

et al. 2015

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Metal-imbalance has been reported as a contributor factor for the degeneration of dopaminergic neurons in Parkinson Disease (PD). Specifically, iron (Fe)-overload and copper (Cu) mis-compartmentalization have been reported to be involved in the injury of dopaminergic neurons in this pathology. The aim of this work was to characterize the mechanisms of membrane repair by studying lipid acylation and deacylation reactions and their role in oxidative injury in N27 dopaminergic neurons exposed to Fe-overload and Cu-supplementation. N27 dopaminergic neurons incubated with Fe (1mM) for 24 hs displayed increased levels of reactive oxygen species (ROS), lipid peroxidation and elevated plasma membrane permeability. Cu-supplemented neurons (10, 50 μM) showed no evidence of oxidative stress markers. A different lipid acylation profile was observed in N27 neurons pre-labeled with [3H] arachidonic acid (AA) or [3H] oleic acid (OA). In Fe-exposed neurons, AA uptake was increased in triacylglycerols (TAG) whereas its incorporation into the phospholipid (PL) fraction was diminished. TAG content was 40% higher in Fe-exposed neurons than in controls. This increase was accompanied by the appearance of Nile red positive lipid bodies. Contrariwise, OA incorporation increased in the PL fractions and showed no changes in TAG. Lipid acylation profile in Cu-supplemented neurons showed AA accumulation into phosphatidylserine and no changes in TAG. The inhibition of deacylation/acylation reactions prompted an increase in oxidative stress markers and mitochondrial dysfunction in Fe-overloaded neurons. These findings provide evidence about the participation of lipid acylation mechanisms against Fe-induced oxidative injury and postulate that dopaminergic neurons cleverly preserve AA in TAG in response to oxidative stress.

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Section: Resultsmentioning

confidence: 99%

Dopaminergic Neurons Respond to Iron-Induced Oxidative Stress by Modulating Lipid Acylation and Deacylation Cycles

et al. 2015

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“…Overexpression of iPLA 2 β in INS-1 insulinoma cells enhanced repair of oxidized mitochondrial cardiolipins (CL) and protected against mitochondria-driven prooxidant cell death 32 . In the retina, an inhibitor of iPLA 2 , bromophenol lactone (BEL), stimulated the accumulation of Fe-induced lipid peroxidation products 33 . Elevated Fe levels, oxidative stress and lipid peroxidation have been implicated in retinal damage in age-related macular degeneration (AMD) 34 .…”

Section: Discussionmentioning

confidence: 99%

Phospholipase iPLA2β averts ferroptosis by eliminating a redox lipid death signal

et al. 2021

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Ferroptosis, triggered by discoordination of iron, thiols and lipids, leads to accumulation of 15-hydroperoxy-arachidonoyl-PE (15-HpETE-PE) generated by complexes of 15-lipoxygenase (15-LOX) and a scaffold protein, PEBP1. As Ca 2+ -independent phospholipase PLA 2 (iPLA 2 β, PLA2G6/PNPLA9 gene), can preferentially hydrolyze peroxidized phospholipids, it may eliminate ferroptotic 15-HpETE-PE death signal. Here we demonstrate that by hydrolyzing 15-HpETE-PE, iPLA 2 β averts ferroptosis whereas its genetic or pharmacological inactivation sensitizes cells to ferroptosis. Given that PLA2G6/PNPLA9 mutations relate to neurodegeneration, we examined fibroblasts from a patient with a Parkinson’s disease (PD)-associated mutation fPD R747W and found selectively decreased 15-HpETE-PE hydrolyzing activity, 15-HpETE-PE accumulation and elevated sensitivity to ferroptosis. CRISPR-CAS9-engineered PNPLA9 R748W/R748W mice exhibited progressive parkinsonian motor deficits and 15-HpETE-PE accumulation. Elevated 15-HpETE-PE levels were also detected in midbrains of rotenone-infused parkinsonian rats and α-synuclein mutant SNCA-A53T mice with decreased iPLA 2 β expression and PD-relevant phenotype. Thus, iPLA 2 β is a new ferroptosis regulator and its mutations may be implicated in PD pathogenesis.

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“…In vitro experiments have shown that cellular oxidative stress induced by iron overload is characterized by increased lipid peroxidation and protein and nucleic acid modifications [ 56 – 59 ]. The presence of a labile iron pool (LIP, redox-active iron bound to low affinity compounds and which determines the iron status of the cell) is the main contributor to oxidative stress during iron overload [ 60 ].…”

Section: Iron and Oxidative Stressmentioning

confidence: 99%

Unraveling the Burden of Iron in Neurodegeneration: Intersections with Amyloid Beta Peptide Pathology

Uranga

Salvador

2018

Oxidative Medicine and Cellular Longevity

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Iron overload is a hallmark of many neurodegenerative processes such as Alzheimer's, Parkinson's, and Huntington's diseases. Unbound iron accumulated as a consequence of brain aging is highly reactive with water and oxygen and produces reactive oxygen species (ROS) or free radicals. ROS are toxic compounds able to damage cell membranes, DNA, and mitochondria. Which are the mechanisms involved in neuronal iron homeostasis and in neuronal response to iron-induced oxidative stress constitutes a cutting-edge topic in metalloneurobiology. Increasing our knowledge about the underlying mechanisms that operate in iron accumulation and their consequences would shed light on the comprehension of the molecular events that participate in the pathophysiology of the abovementioned neurodegenerative diseases. In this review, current evidences about iron accumulation in the brain, the signaling mechanisms triggered by metal overload, as well as the interaction between amyloid β (Aβ) and iron, will be summarized.

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Differential participation of phospholipase A2 isoforms during iron-induced retinal toxicity. Implications for age-related macular degeneration

Cited by 12 publications

References 53 publications

Dopaminergic Neurons Respond to Iron-Induced Oxidative Stress by Modulating Lipid Acylation and Deacylation Cycles

Dopaminergic Neurons Respond to Iron-Induced Oxidative Stress by Modulating Lipid Acylation and Deacylation Cycles

Phospholipase iPLA2β averts ferroptosis by eliminating a redox lipid death signal

Unraveling the Burden of Iron in Neurodegeneration: Intersections with Amyloid Beta Peptide Pathology

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