Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Age Related Macular Degeneration, Role in Pathophysiology, and Possible New Therapeutic Strategies

Abstract

Age related macular degeneration (AMD) is the main cause of legal blindness in developed countries. It is a multifactorial disease in which a combination of genetic and environmental factors contributes to increased risk of developing this vision-incapacitating condition. Oxidative stress plays a central role in the pathophysiology of AMD and recent publications have highlighted the importance of mitochondrial dysfunction and endoplasmic reticulum stress in this disease. Although treatment with vascular endothelium growth factor inhibitors have decreased the risk of blindness in patients with the exudative form of AMD, the search for new therapeutic options continues to prevent the loss of photoreceptors and retinal pigment epithelium cells, characteristic of late stage AMD. In this review, we explain how mitochondrial dysfunction and endoplasmic reticulum stress participate in AMD pathogenesis. We also discuss a role of several antioxidants (bile acids, resveratrol, melatonin, humanin, and coenzyme Q10) in amelioration of AMD pathology.

Keywords: age related macular degeneration; antioxidants; bile acids; coenzyme Q10; endoplasmic reticulum; humanin; melatonin; mitochondria; oxidative stress; resveratrol.

Figure 1

Representative retinographies and optical coherence tomography (OCT) of and eye with wet AMD and an eye with dry AMD. (Top row): Color fundus retinography, autofluorescence and OCT of the left eye of a patient presenting wet AMD. In retinography, choroidal neovascularization (CNV) can be seen as a grayish region covering the central macular area. Autofluorescece imaging shows a mixed pattern of hyperautofluorescence and hypoautofluorescence. On OCT the CNV can be clearly visualized as a hyperreflective layer under the retina with intraretinal fluid visualized as multiple hyporeflective spaces. (Bottom row): Color fundus retinography, autofluorescence, and OCT of the left eye of a patient presenting advanced dry AMD. In the retinography an area of central atrophy can be observed in the central macular area that allows better visualization of the choroidal vessels and is surrounded by multiple drusen. Autofluorescence clearly distinguishes the borders of the geographic atrophy due to hypoautofluorescence secondary to the retinal pigment epithelium (RPE) atrophy. OCT reveals atrophy of the RPE and outer retinal layers, with increased signal in the choroid and sclera. The green line represents the OCT section location.

Figure 2

Gross architecture of a eukaryotic cell.

Figure 3

Recognition, retro-translocation, polyubiquitination, and proteasomal degradation of soluble ERAD Substrates. (i) Recognition of misfolded proteins by the ER-resident chaperones like BiP targeting them for retro-translocation. (ii) Initiation of retro-translocation crossing the Hrd1 complex, constituted by several subunits such as Hrd1, Hrd3, Der1, and Usa1; other subunits are not represented. (iii) The catalytic domain of Hrd1 polyubiquitinates the emerging protein in the cytosol. (iv) Further retro-translocation and polyubiquitination aided by cytoplasmic ubiquitin-binding protein complexes (not shown). (v) Proteasome degradation where the protein is broken down into peptide fragments.

Figure 4

Schematic illustration of reticulophagy. Reticulophagy receptors FAM134B/ATL3 present in the surface of the ER-membrane are recognized by ATG8/LC3/GABARAP proteins in the surface of the phagophore. As a result of this interaction fragments of the ER are enclosed by the phagophore, forming an autophagosome, which delivers the enclosed ER fragments to the lysosome for degradation.

Figure 5

Activation of the unfolded protein response (UPR). The accumulation of misfolded proteins in the ER leads to the dissociation of BiP from the three ER-stress sensor PERK, IRE-1 and ATF6 and activates the coordinated unfolded protein response. ATF6 is translocated to the Golgi where it undergoes sequential cleavage and migrates to the nucleus. IRE-1 and PERK are activated by oligomerization and trans-phosphorylation. The IRE-1 endoribonuclease activity splices out an intron on XBP1 mRNA to generate XBP1s. IRE-1 also triggers the JNK pathway. PERK phosphorylates eIF2α (not shown) and enhance the translation of ATF4 which upregulates CHOP. The integrated signaling of this three sensor regulates mRNAs decay, attenuates translation, increases chaperon sintesis, upregulates the antioxidante response, and promotes ERAD and reticulophagy. Sustained hyperactivation leads to apoptosis.