Abstract
Age-related macular degeneration (AMD) is the leading cause of severe and irreversible vision loss and is characterized by progressive degeneration of the retina resulting in loss of central vision. The retinal pigment epithelium (RPE) is a critical site of pathology of AMD. Mitochondria and the endoplasmic reticulum which lie in close anatomic proximity to each other are targets of oxidative stress and endoplasmic reticulum (ER) stress, respectively, and contribute to the progression of AMD. The two organelles exhibit close interactive function via various signaling mechanisms. Evidence for ER-mitochondrial crosstalk in RPE under ER stress and signaling pathways of apoptotic cell death is presented. The role of humanin (HN), a prominent member of a newly discovered family of mitochondrial-derived peptides (MDPs) expressed from an open reading frame of mitochondrial 16S rRNA, in modulation of ER and oxidative stress in RPE is discussed. HN protected RPE cells from oxidative and ER stress-induced cell death by upregulation of mitochondrial GSH, inhibition of ROS generation, and caspase 3 and 4 activation. The underlying mechanisms of ER-mitochondrial crosstalk and modulation by exogenous HN are discussed. The therapeutic use of HN and related MDPs could potentially prove to be a valuable approach for treatment of AMD.
Highlights
Age-related macular degeneration (AMD) is the leading cause of severe and irreversible vision loss and is characterized by progressive degeneration of the retina resulting in loss of central vision
It is of interest that in cardiac myoblasts stressed with H2O2, it was reported that HN analog (HNG) preserved mitochondrial membrane potential and mitochondrial structural integrity and inhibited mitochondrial swelling [74]
We present a composite scheme that depicts the endoplasmic reticulum (ER)-mitochondrial crosstalk in cellular stress and the protective role played by HN in retinal pigment epithelium (RPE) cell death by ER and oxidant stressors by direct and indirect mechanisms (Figure 2)
Summary
Age-related macular degeneration (AMD) is a progressive degenerative retinal disease that impairs visual acuity and causes irreversible central vision loss. The early phase of the disease may progress into either of the two advanced AMD subtypes: geographic/atrophic AMD (“dry AMD” or GA) with loss of retinal pigment epithelium (RPE) cells and photoreceptors or exudative/neovascular AMD (or “wet AMD”), which is distinguished from the former by the presence of choroidal neovascularization (CNV) [4]. These subtypes are not mutually exclusive as patients may exhibit characteristics of both dry and wet AMD in one eye, dry in one eye and wet in the other, and even the evolution of dry to wet AMD and vice versa [5]. Neovascular AMD is characterized by abnormal growth of immature and leaky choroidal vessels through BM which is associated with increased expression of vascular endothelial growth factor (VEGF) [1]
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