Increased retinal mtDNA damage in the CFH variant associated with age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is a major cause of blindness among the elderly in the developed world. Genetic analysis of AMD has identified 34 high-risk loci associated with AMD. The genes at these high risk loci belong to diverse biological pathways, suggesting different mechanisms leading to AMD pathogenesis. Thus, therapies targeting a single pathway for all AMD patients will likely not be universally effective. Recent evidence suggests defects in mitochondria (mt) of the retinal pigment epithelium (RPE) may constitute a key pathogenic event in some AMD patients. The purpose of this study is to determine if individuals with a specific genetic background have a greater propensity for mtDNA damage. We used human eyebank tissues from 76 donors with AMD and 42 age-matched controls to determine the extent of mtDNA damage in the RPE that was harvested from the macula using a long extension polymerase chain reaction assay. Genotype analyses were performed for ten common AMD-associated nuclear risk alleles (ARMS2, TNFRSF10A, CFH, C2, C3, APOE, CETP, LIPC, VEGF and COL10A1) and mtDNA haplogroups. Sufficient samples were available for genotype association with mtDNA damage for TNFRSF10A, CFH, CETP, VEGFA, and COL10A1. Our results show that AMD donors carrying the high risk allele for CFH (C) had significantly more mtDNA damage compared with donors having the wild-type genetic profile. The data from an additional 39 donors (12 controls and 27 AMD) genotyped for CFH alleles further supported these findings. Taken together, these studies provide the rationale for a more personalized approach for treating AMD by uncovering a significant correlation between the CFH high risk allele and accelerated mtDNA damage. Patients harboring this genetic risk factor may benefit from therapies that stabilize and protect the mt in the RPE.

Repository of proposed pathways and protein–protein interaction networks in age-related macular degeneration

“…Mitochondrial DNA is particularly susceptible to oxidative damage in human RPE. 26 Combined with the reduction of cellular antioxidant system capacity due to aging 27 it seems likely that mitochondria will have an important role in the pathogenesis of AMD and so we considered it important to include mitochondria in the graphical representation (see Data Availability, Supplementary File 2). The accumulation of macrophages is described as a feature of early and late AMD, 25 and although the role of macrophages in pathogenesis is not fully defined, we considered it important to include a subretinal macrophage submodule (see Data Availability, Supplementary File 3).…”

Mitochondria-dependent phase separation of disease-relevant proteins drives pathological features of age-related macular degeneration

“…observed in AMD donor RPE (55,56,58,79), and our studies provide a molecular mechanism to explain how AMD-associated cholesterol pathway genes can drive these phenotypes.…”

“…In contrast, mitochondria in ApoE2-expressing RPE were fragmented in response to NHS ( Figures 3A and 3B These data provide further evidence for multilayered crosstalk between cholesterol and complement pathways in maintaining or endangering RPE metabolic health, and yet again, demonstrate that genetic variants or pharmacological approaches that limit excess cholesterol safeguard RPE mitochondrial integrity. In support of this, epidemiological and genetic studies show that high HDL cholesterol is associated with increased complement activation in AMD patients (57), and abnormal complement activation is accompanied by mitochondrial dysfunction in AMD donor RPE (58).…”

“…Donor 2 (unaffected) and donor 4 (with AMD) both had the E3/E3 genotype but differed in almost all other major AMD risk alleles (Table S1). A major difference was that the unaffected donor had the non-risk CFH allele, whereas the AMD donor had the Y402H allele, which has been associated with increased mitochondrial DNA damage (58). The complex genetics and multifactorial etiology of AMD make it challenging to ascribe individual genetic polymorphisms to specific disease phenotypes (8).…”

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

“…A disruption of either mitochondria or glycolytic function can lead to a failure in the metabolic system. Loss of CFH has been associated with mitochondria impairment in retinal development in a CFH Knock-out mouse model [52] and patients carrying the CFH H402 high-risk variant present increased mitochondrial DNA damage [53]. Whether FH contributes to metabolic homeostasis of RPE cells has never been investigated.…”