Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Nov:79:100858.
doi: 10.1016/j.preteyeres.2020.100858. Epub 2020 Apr 13.

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

Kai Kaarniranta  1 , Hannu Uusitalo  2 , Janusz Blasiak  3 , Szabolcs Felszeghy  4 , Ram Kannan  5 , Anu Kauppinen  6 , Antero Salminen  7 , Debasish Sinha  8 , Deborah Ferrington  9
Affiliations
Review

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

Kai Kaarniranta et al. Prog Retin Eye Res. 2020 Nov.

Abstract

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.

Keywords: Age-related macular degeneration; Aggregation; Aging; Autophagy; Clearance; Degeneration; Mitochondria; Mitophagy; Retina; Retinal pigment epithelium.

PubMed Disclaimer

Figures

Fig. 1.
Fig. 1.
Mitochondrial DNA (mtDNA) in the neural retina and retinal pigment epithelial (RPE) cells can be damaged by many endogenous and exogenous factors, including some risk factors of age-related macular degeneration (AMD). Aging, the primary AMD risk factor, is also associated with induction of mtDNA damage. It is likely that mtDNA damage affects genes encoding the mitochondrial electron transport chain resulting in reactive oxygen species (ROS) overproduction, leading to more damage to mtDNA. These changes can be counterbalanced by efficient (+) antioxidant enzymes or DNA repair, but when these systems fail, accumulated damage to mtDNA can result in mitochondrial dysfunctions, energy crisis, cell degeneration and death observed in AMD.
Fig. 2.
Fig. 2.
Dry age-related macular degeneration: symptoms and signs. (A) Color fundus photograph from normal and dry AMD patient maculas. The central macula controls sharp and color vision (white ring). Drusen are the clinical hallmarks of AMD (dark ring). (B) Optical coherent tomography (OCT) from the healthy and AMD retinas. Arrows indicate different layers of the retina: 1) external limiting membrane, 2) ellipsoid layer, 3) RPE layer, 4) retinal nerve fiber layer (RNFL), 5) ganglion cell layer, 6) inner plexiform layer, 7) inner nuclear layer, 8) outer plexiform layer 9) outer nuclear layer. (C) Representative vision disturbances during the progression of AMD. (D) Light microscopic image of hematoxylin-eosin (HE) stained human retina from (D, left panel) healthy and (E, left panel) AMD donors. High power confocal images indicate extracellular ubiquitin (Ubq, middle panels) and intracellular p62 (right panels) stainings. Arrowheads show drusen accumulation.
Fig. 3.
Fig. 3.
RPE from donors with AMD show reduced mitochondrial function. (A) Trace from an XF96 Extracellular Flux Analyzer shows the oxygen consumption rate (OCR) normalized to baseline for cells from non-diseased and AMD donors (No AMD n = 14; AMD n = 19). Arrows indicate injection of oligomycin (1), FCCP (2) and antimycin and rotenone (3) to perturb mitochondrial function. (B) Mitochondrial functional parameters were calculated from data shown in A. Probability values for significant differences, as determined by t-test comparing No AMD with AMD, is provided on the graphs. Bas Res = basal respiration; Max Res = maximal respiration; Sp Cap = spare capacity. All data are mean (±SEM). (* denotes p < 0.05). Data shown is similar to that in Ferrington et al. (2017), Redox Biol. publication.
Fig. 4.
Fig. 4.
Fundus autofluorescence (FAF) image from a patient suffering geographic atrophy (GA; white arrows) in advanced AMD. Yellow arrows indicate increased autofluorescence due to lipofuscin accumulation and drusen. Photograph by Kai Kaarniranta.
Fig. 5.
Fig. 5.
The PINK1-Parkin-regulated mitophagy. Chronic oxidative stress and ROS evokes misfolding of proteins in RPE cells. Heat-shock proteins (Hsps) attempt to refold damaged proteins, but if not successful, the misfolded proteins are ubiquitinated (Ubq) and targeted for proteasomal clearance. Once proteasome activity is decreased or its capacity exceeded, proteins start to aggregate and are degraded via autophagy. Mitochondrial damage results in the accumulation of PINK1 and the activation of Parkin. Mitophagy receptors, such as OPTN (optineurin), TAXBP1 (Tax-1-binding protein 1), NDP52 (nuclear domain 10 protein 52), p62 and NBR1 (Neighbor of BRCA1 gene 1 protein), and contains an ubiquitin-binding site that allows their attachment to Parkin-ubiquitinated mitochondria. This process initiates the phagophore formation leading to sealed material degradation. Rab 5 and Rab7 control endosome maturation that finally leads to fusion of lysosomes and autophagosomes.
Fig. 6.
Fig. 6.
A transmission electron micrograph shows damaged mitochondria enclosed by autophagosome (arrow) in the RPE of a 20-month-old Cryba1 knockout mouse. The scale bar = 500 μm. The electron micgraph has been modified from the Sinha et al. (2016) Exp. Eye Res. publication.
Fig. 7.
Fig. 7.
Schematic presentation of the oxidative stress influence on AMPK, NFE2L2, PGC-1 α, and autophagy pathway interactions in RPE. In response to oxidative stress, AMPK is phosphorylated, which subsequently phosphorylates NFEL2L and PGC-1α leading to their nuclear translocation and activation of genes that regulate mitochondrial biogenesis and antioxidant protein production. NFEL2L and PGC-1α also have a key role in the regulation of autophagy. Failure in AMPK –mediated signaling leads to disturbed proteostasis in RPE cells.
Fig. 8.
Fig. 8.
Increased protein aggregation (Ubiquitin), autophagy (p62/SQSTM1, Beclin-1, LC3B) and oxidative stress (4-HNE) markers in the RPE cells of PGC-1α KO, NFE2L2 KO and NFE2L2/PGC-1α dKO mice. Data represent average intensities from three different animals per genotype and n = 30. *p < 0.001 one-way ANOVA followed by Games-Howell post hoc test. Results are expressed as means ± SD. Colums represent similar results shown in the Felszeghy et al. (2019) Redox Biology publication.
Fig. 9.
Fig. 9.
The pathological changes of RPE in NFE2L2/PGC-1α dKO mice. The representative confocal microscopic images of one-year old (A–D) and (H–K) dKO samples indicate various dry AMD resembling signs. The accumulation of intracellular lipofuscin-like material (white arrowhead; H), extracellular ubiquitin (Ubg) positivity (read arrowhead; I), restricted apoptosis (green arrow; J) and outer nuclear layer (ONL) atrophy (K) can be observed in the dKO samples. The TEM images of the WT (E–G) and dKO (L–O) samples. The basal folding of RPE is well-preserved in WT (E,G), while their disruption occurs in dKO (L,O). The thicker-disrupted Bruch's membrane (BM) of the dKO sample is shown in image L (black arrow), where electron-dense amorphous debris (yellow arrrow; O) and the membranous debris (blue arrowhead) are abundant compared to the WT sample (G). Alterations of microvilli structures (blue arrow; E,L), increased number of melanin pigments (red arrowheads; F,M), the damaged photoreceptor layer (E,L), enlarged vacuole-like structures (pink arrow; L and blue arrows; F,M) are more visible in dKO. N means nuclei and E endothelial cell nuclei. The scale bars for A, H = 5 μm, B, I and I–K = 2 μm, C, J = 5 μm, D, K = 2 μm, E,L = 5 μm, F, M and G, O Data represent similar results shown in the Felszeghy et al. (2019) Redox Biology publication.
Fig. 10.
Fig. 10.
Graphical summary of the AMD hallmarks detected in one-year-old NFE2L2/PGC-1α gene modified mice. Summary modified from the Felszeghy et al. (2019) Redox Biology publication.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ach T, Huisingh C, McGwin G Jr., Messinger JD, Zhang T, Bentley MJ, Gutierrez DB, Ablonczy Z, Smith RT, Sloan KR, Curcio CA, 2014. Quantitative autofluorescence and cell density maps of the human retinal pigment epithelium. Invest. Ophthalmol. Vis. Sci 55, 4832–4841. - PMC - PubMed
    1. Ach T, Tolstik E, Messinger JD, Zarubina AV, Heintzmann R, Curcio CA, 2015. Lipofuscin redistribution and loss accompanied by cytoskeletal stress in retinal pigment epithelium of eyes with age-related macular degeneration. Invest. Ophthalmol. Vis. Sci 56, 3242–3252. - PMC - PubMed
    1. Alaimo A, Liñares GG, Bujjamer JM, Gorojod RM, Alcon SP, Martínez JH, Baldessari A, Grecco HE, Kotler ML, 2019. Toxicity of blue led light and A2E is associated to mitochondrial dynamics impairment in ARPE-19 cells: implications for age-related macular degeneration. Arch. Toxicol 93, 1401–1415. - PubMed
    1. Allio R, Donega S, Galtier N, Nabholz B, 2017. Large variation in the ratio of mitochondrial to nuclear mutation rate across animals: implications for genetic diversity and the use of mitochondrial DNA as a molecular marker. Mol. Biol. Evol 34, 2762–2772. - PubMed
    1. Ames BN, Shigenaga MK, 1992. Oxidants are a major contributor to aging. Ann. N. Y. Acad. Sci 21, 85–96. - PubMed

Publication types