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

Armento, Angela; Honisch, Sabina; Panagiotakopoulou, Vasiliki; Sonntag, Inga; Jacob, Anke; Kilger, Ellen; Deleidi, Michela; Clark, Simon J.; Ueffing, Marius

doi:10.1101/2020.01.08.898551

Cited by 4 publications

(8 citation statements)

References 66 publications

(79 reference statements)

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“…Evidence linking genetic backgrounds with elevated oxidative stress included the significantly higher RPE mtDNA damage reported in donors harboring the CFH high risk alleles ( Ferrington et al, 2016a ). Dysfunctional CFH reduces antioxidant capacity and energy metabolism of human RPE cells ( Armento et al, 2020 ). Additionally, the presence of the ARMS2/HTRA1 risk alleles in induced pluripotent stem-RPE cells (iPSC-RPE) resulted in decreased antioxidant defenses, thereby making the RPE more susceptible to oxidative damage ( Yang et al, 2014 ).…”

Section: Introduction To Rpe Degeneration and Development Of Amdmentioning

confidence: 99%

Mechanisms of mitochondrial dysfunction and their impact on age-related macular degeneration

Kaarniranta

Uusitalo

Błasiak

et al. 2020

Progress in Retinal and Eye Research

257

192

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Oxidative stress-induced damage to the retinal pigment epithelium (RPE) is considered to be a key factor in age-related macular degeneration (AMD) pathology. RPE cells are constantly exposed to oxidative stress that may lead to the accumulation of damaged cellular proteins, lipids, nucleic acids, and cellular organelles, including mitochondria. The ubiquitin-proteasome and the lysosomal/autophagy pathways are the two major proteolytic systems to remove damaged proteins and organelles. There is increasing evidence that proteostasis is disturbed in RPE as evidenced by lysosomal lipofuscin and extracellular drusen accumulation in AMD. Nuclear factor-erythroid 2-related factor-2 (NFE2L2) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) are master transcription factors in the regulation of antioxidant enzymes, clearance systems, and biogenesis of mitochondria. The precise cause of RPE degeneration and the onset and progression of AMD are not fully understood. However, mitochondria dysfunction, increased reactive oxygen species (ROS) production, and mitochondrial DNA (mtDNA) damage are observed together with increased protein aggregation and inflammation in AMD. In contrast, functional mitochondria prevent RPE cells damage and suppress inflammation. Here, we will discuss the role of mitochondria in RPE degeneration and AMD pathology focused on mtDNA damage and repair, autophagy/mitophagy signaling, and regulation of inflammation. Mitochondria are putative therapeutic targets to prevent or treat AMD.

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Section: Introduction To Rpe Degeneration and Development Of Amdmentioning

confidence: 99%

Mechanisms of mitochondrial dysfunction and their impact on age-related macular degeneration

Kaarniranta

Uusitalo

Błasiak

et al. 2020

Progress in Retinal and Eye Research

257

192

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“…Additionally, generation of complement activation products, such as anaphylatoxins and opsonins, by healthy and stressed RPE cells independent of any external complement source is described [ 21 , 24 , 26 , 27 ]. Recently, it was reported, that endogenous CFH and anaphylatoxins contribute to transcriptional and metabolic homeostasis of RPE cells [ 28 , 29 , 30 ]. In RPE cells complement anaphylatoxins receptor signaling is involved in eye morphogenesis [ 31 ], sub-RPE deposits [ 32 ], pro-inflammatory RPE reaction [ 33 , 34 , 35 ], PI3/Akt-pathway activation [ 29 ], and stress-mediated lipid accumulation in RPE cells [ 36 ].…”

Section: Introductionmentioning

confidence: 99%

Properdin Modulates Complement Component Production in Stressed Human Primary Retinal Pigment Epithelium Cells

et al. 2020

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The retinal pigment epithelium (RPE) maintains visual function and preserves structural integrity of the retina. Chronic dysfunction of the RPE is associated with retinal degeneration, including age-related macular degeneration (AMD). The AMD pathogenesis includes both increased oxidative stress and complement dysregulation. Physiological sources of oxidative stress in the retina are well known, while complement sources and regulation are still under debate. Using human primary RPE (hpRPE) cells, we have established a model to investigate complement component expression on transcript and protein level in AMD-risk and non-risk hpRPE cells. We evaluated the effect of properdin, a complement stabilizer, on the hpRPE cell-dependent complement profile exposed to oxidative stress. hpRPE cells expressed complement components, receptors and regulators. Complement proteins were also stored and secreted by hpRPE cells. We associated AMD-risk single nucleotide polymorphisms with an increased secretion of complement factors D (CFD) and I (CFI). Furthermore, we detected hpRPE cell-associated complement activation products (C3a, C5a) independent of any extracellularly added complement system. Exogenous properdin increased the mRNA expression of CFI and CFD, but decreased levels of complement components (C1Q, C3), receptors (C3AR, C5AR1, CD11B) and inflammation-associated transcripts (NLRP3, IL1B) in hpRPE cells exposed to oxidative stress. This properdin effect was time-dependently counter regulated. In conclusion, our data unveiled a local, genotype-associated complement component production in hpRPE cells, regulated by exogenous properdin. The local complement production and activation via blood-independent mechanisms can be a new therapeutic target for AMD.

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“…Furthermore, mitochondrial function, based on oxygen consumption rates, was impaired potentially explaining why exogeneous FH did not rescue the observed effects. 100 In contrast, supplementation of recombinant FH to ARPE-19 cells resulted in significantly reduced cell death when adding FH p.402Tyr but not when adding FH p.402His. The protective effect of FH p.402Tyr was further confirmed in iPSC-derived RPE cells.…”

Section: Invitroanalys Isofcomplement Inre Tinalcellt Ype Smentioning

confidence: 93%

“…Interestingly, addition of exogeneous FH did not provide protection from these effects. Furthermore, mitochondrial function, based on oxygen consumption rates, was impaired potentially explaining why exogeneous FH did not rescue the observed effects 100 . In contrast, supplementation of recombinant FH to ARPE‐19 cells resulted in significantly reduced cell death when adding FH p.402Tyr but not when adding FH p.402His.…”

Section: In Vitro Analysis Of Complement In Retinal Cell Typesmentioning

confidence: 98%

“…Complementing the data generated by Armento et al, who used ARPE‐19 cells, 100 Hallam et al also observed mitochondrial stress in iPSC‐derived RPE cell lines carrying the high‐risk variant p.Tyr402His in CFH based on mitochondria being reduced in quantity, but showing increased volume 109 . Impairment of mitochondrial function in both primary RPE and iPSC‐derived RPE derived from AMD patients has been confirmed in multiple studies, 110,112,113 but interestingly in a more recent study mitochondrial impairment was linked to the CFH risk genotype at p.Tyr402His independent of the donor's phenotype 114 .…”

Section: In Vitro Analysis Of Complement In Retinal Cell Typesmentioning

confidence: 99%

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Age‐related macular degeneration: A disease of extracellular complement amplification

Jong

Tang

Clark

2022

Immunological Reviews

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Western world, with more than 10% of individuals above 70 years affected in Europe. 1 Due to the increasing age of the general population, the number of AMD patients is expected to increase in the coming years, posing a major burden for healthcare systems. 2 The affected tissue in AMD is the macula, which is the part of the retina involved in central vision (Figure 1). The retina is a layered structure consisting of the following layers listed from anterior to posterior: ganglion cell layer (ganglion cells), inner plexiform layer (neuronal synapses connecting bipolar cells, amacrine cells, and retinal ganglion cells), inner nuclear layer (nuclei of bipolar, amacrine, horizontal, and Müller cells), outer plexiform layer (neuronal synapses connecting from photoreceptor cells, horizontal cells, and bipolar cells), and the outer nuclear layer (photoreceptor cell nuclei). 3 Adjacent to the photoreceptor outer segments, is the retinal pigment epithelium (RPE), which supports photoreceptor function by phagocytosing outer segments, providing growth factors and nutrients. Additionally, the RPE forms together with its underlying extracellular matrix (ECM) called Bruch's membrane (BrM), the outer blood/retinal barrier. 4 AMD patients often experience blurred or shadowed central vision as first symptoms. Characteristics for the clinical diagnosis

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

Cited by 4 publications

References 66 publications

Mechanisms of mitochondrial dysfunction and their impact on age-related macular degeneration

Mechanisms of mitochondrial dysfunction and their impact on age-related macular degeneration

Properdin Modulates Complement Component Production in Stressed Human Primary Retinal Pigment Epithelium Cells

Age‐related macular degeneration: A disease of extracellular complement amplification

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