Understanding membrane remodelling initiated by photosensitized lipid oxidation

Tsubone, Tayana Mazin; Baptista, Maurício da Silva; Itri, Rosângela

doi:10.1016/j.bpc.2019.106263

Cited by 54 publications

(62 citation statements)

References 191 publications

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“…Interestingly, either FH loss or H 2 O 2 treatment alone, had no negative effects on viability or lipid peroxidation, confirming the importance of risk factor combinations in RPE cell degeneration during AMD pathology. www.nature.com/scientificreports www.nature.com/scientificreports/ Lipid oxidation also affects membrane permeability 56 and exogenous FH helps maintain a ZO-1 localization in response to 4-HNE in ARPE19 cells 21 . In our model, we show that reduction of endogenous FH mediates cell membrane damage in RPE cells.…”

Section: Discussionmentioning

confidence: 99%

Loss of Complement Factor H impairs antioxidant capacity and energy metabolism of human RPE cells

Armento

Honisch

Panagiotakopoulou

et al. 2020

Sci Rep

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polymorphisms in the complement factor H (CFH) gene, coding for the factor H protein (fH), can increase the risk for age-related macular degeneration (AMD). AMD-associated CFH risk variants, Y402H in particular, impair FH function leading to complement overactivation. Whether this alone suffices to trigger AMD pathogenesis remains unclear. in AMD, retinal homeostasis is compromised due to the dysfunction of retinal pigment epithelium (Rpe) cells. to investigate the impact of endogenous fH loss on Rpe cell balance, we silenced CFH in human hTERT-RPE1 cells. FH reduction led to accumulation of C3, at both RNA and protein level and increased RPE vulnerability toward oxidative stress. Mild hydrogen-peroxide exposure in combination with CFH knock-down led to a reduction of glycolysis and mitochondrial respiration, paralleled by an increase in lipid peroxidation, which is a key aspect of AMD pathogenesis. in parallel, cell viability was decreased. the perturbations of energy metabolism were accompanied by transcriptional deregulation of several glucose metabolism genes as well as genes modulating mitochondrial stability. our data suggest that endogenously produced fH contributes to transcriptional and metabolic homeostasis and protects Rpe cells from oxidative stress, highlighting a novel role of fH in AMD pathogenesis. Retinal pigment epithelium (RPE) cells are crucial for the maintenance of retinal homeostasis. RPE cells are located on a thin membrane called Bruch´s membrane (BM), and together provide a barrier between the neuroretina and the choroid capillary network. In addition, RPE cells fulfil several key functions, such as phagocytosis of the photoreceptor outer segments, transport of nutrients, preservation of the retinal structure and, most importantly, due to their high antioxidant capacity, RPE cells protect the retina from photo-oxidation and oxidative damage 1. RPE dysfunction and degeneration are key features of age-related macular degeneration (AMD), a complex degenerative disease, and the primary cause of blindness in the elderly population 2. AMD is characterized by a progressive degeneration of the macula, the cone-rich area of the retina, where damage in this area leads to central vision loss and ultimately blindness 3. The aetiology of AMD involves ageing processes, genetic predisposition and environmental factors, however a full understanding of AMD pathogenesis is lacking, which makes drug discovery challenging 4. A defining hallmark of AMD is the presence of deposits, called drusen, between the BM and the RPE layer 5. In the presence of drusen or altered extracellular matrix (ECM) of BM, the functionality of RPE cells may be impaired 6. The retinal microenvironment is already highly oxidized in physiological conditions, due to a very high energy demand and photo-oxidation. Ageing processes, in combination with external stressors including smoking or a high fat diet 7,8 , force RPE cells to deal with excessive levels of oxidative stress. Disturbed RPE cell homeostasis, and in particular RPE cell ...

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Section: Discussionmentioning

confidence: 99%

Loss of Complement Factor H impairs antioxidant capacity and energy metabolism of human RPE cells

Armento

Honisch

Panagiotakopoulou

et al. 2020

Sci Rep

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“…Computational and experimental studies show that the bending of the fatty acyl chain results in a 15–20% increase in membrane surface area upon full conversion of POPC or 1,2-dioleoyl- sn -glycero-3-phosphocholine (DOPC) to hydroperoxides (Figure 3A), which is accompanied by a 15–20% decrease in membrane thickness. 5,22 Even though several other transformations were reported to occur due to the formation of lipid hydroperoxides (e.g., changes in lipid lateral phase separation behavior 23 and a ca. 4-fold decrease in the membrane stretching modulus 14 ), full conversion of monounsaturated lipids to hydroperoxides does not permeabilize the membrane toward sugars or cause pore opening, as observed in experiments with GUVs and also in computational simulations of membranes (Figure 3B).…”

Section: Photosensitized Oxidations In the Context Of Lipid Oxidationmentioning

confidence: 99%

“…Simulations typically require higher concentrations of oxidized lipids for pores to be observed in comparison to experimental studies. One possible cause of this discrepancy is the fact that membranes may exhibit lipid phase separation, 23 having nano- or microsized domains that may concentrate oxidized lipids to levels more compatible with simulations. Discrepancies could also arise from the membranes oxidized in situ being under nonequilibrium conditions and susceptible to forces that may contribute to pore opening.…”

Section: Lipid Truncated Aldehydes and Membrane Permeabilizationmentioning

confidence: 99%

Mechanisms of Photosensitized Lipid Oxidation and Membrane Permeabilization

2019

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Lipid oxidation encompasses chemical transformations affecting animals and plants in many ways, and light is one of the most common triggers of lipid oxidation in our habitat. Still, the molecular mechanisms and biological consequences of photoinduced lipid oxidation were only recently understood at the molecular level. In this review, we focus on the main mechanisms of photosensitized lipid oxidation and membrane permeabilization, dissecting the consequences of both singlet oxygen and contact-dependent pathways and discussing how these reactions contribute to chemical and biophysical changes in lipid membranes. We aim to enable scientists to develop novel and more efficient photosensitizers in photomedicine, as well as better strategies for sun protection.

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“…As a consequence, cell viability of RPE cells is affected only in this condition. Lipid oxidation also affects membrane permeability [51] and exogenous FH helps maintain a ZO-1 localization in response to 4-HNE in ARPE19 cells [50]. In our model, we show that reduction of endogenous FH mediates cell membrane damage in RPE cells.…”

Section: Discussionmentioning

confidence: 65%

Loss of Complement Factor H impairs antioxidant capacity and energy metabolism of human RPE cells

Armento¹,

Honisch²,

Panagiotakopoulou

et al. 2020

Preprint

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Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly population. About 50% of AMD patients present polymorphisms in the Complement Factor H (CFH) gene, coding for Factor H protein (FH). AMD-associated CFH risk variants, Y402H in particular, impair FH function leading to complement overactivation. In AMD, retinal homeostasis is compromised due to dysfunction of retinal pigment epithelium (RPE) cells. Whether FH contributes to AMD pathogenesis only via complement system dysregulation remains unclear. To investigate the potential role of FH on energy metabolism and oxidative stress in RPE cells, we silenced CFH in human hTERT-RPE1 cells. FH-deprived RPE cells exposed to oxidative insult, showed altered metabolic homeostasis, including reduction of glycolysis and mitochondrial respiration, paralleled by an increase in lipid peroxidation. Our data suggest that FH protects RPE cells from oxidative stress and metabolic reprogramming, highlighting a novel function for FH in AMD pathogenesis.Graphical abstract

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Understanding membrane remodelling initiated by photosensitized lipid oxidation

Cited by 54 publications

References 191 publications

Loss of Complement Factor H impairs antioxidant capacity and energy metabolism of human RPE cells

Loss of Complement Factor H impairs antioxidant capacity and energy metabolism of human RPE cells

Mechanisms of Photosensitized Lipid Oxidation and Membrane Permeabilization

Loss of Complement Factor H impairs antioxidant capacity and energy metabolism of human RPE cells

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