Role of Mitochondria in Retinal Pigment Epithelial Aging and Degeneration

Abstract

Retinal pigment epithelial (RPE) cells form a monolayer between the neuroretina and choroid. It has multiple important functions, including acting as outer blood-retina barrier, maintaining the function of neuroretina and photoreceptors, participating in the visual cycle and regulating retinal immune response. Due to high oxidative stress environment, RPE cells are vulnerable to dysfunction, cellular senescence, and cell death, which underlies RPE aging and age-related diseases, including age-related macular degeneration (AMD). Mitochondria are the powerhouse of cells and a major source of cellular reactive oxygen species (ROS) that contribute to mitochondrial DNA damage, cell death, senescence, and age-related diseases. Mitochondria also undergo dynamic changes including fission/fusion, biogenesis and mitophagy for quality control in response to stresses. The role of mitochondria, especially mitochondrial dynamics, in RPE aging and age-related diseases, is still unclear. In this review, we summarize the current understanding of mitochondrial function, biogenesis and especially dynamics such as morphological changes and mitophagy in RPE aging and age-related RPE diseases, as well as in the biological processes of RPE cellular senescence and cell death. We also discuss the current preclinical and clinical research efforts to prevent or treat RPE degeneration by restoring mitochondrial function and dynamics.

Keywords: RPE; age-related macula degeneration; aging; cell death; degeneration; mitochondria; senescense.

FIGURE 1

RPE changes during aging: Young RPE cell shows elongated microvilli, tight contact with nearby cells, containing plenty of mitochondria, melanin granules and photoreceptor fragments. Aged RPE cell shows larger size, multinucleation, shortened microvilli, decreased mitochondria numbers, loss of melanin granules, decreased phagocytosis, accumulation of lipofuscin and iron, basal laminar deposits, increased BrM thickness and accumulation of drusen.

FIGURE 2

Comparison of mitochondria in young, aged and AMD RPE: (A) Young RPE cell contains numerous mitochondria with long axes, usually oriented from the apical to the basal surfaces of the RPE and are parallel to one another. The mitochondrial cristae are well preserved. Several peroxisomes appeared as small, round, electron-dense organelles. Plenty of melanin granules exist in the cells. (B) In aged RPE cell, mitochondria show membrane disorganization and loss of cristae. Accumulated lipofuscin presents in the cell. Several peroxisomes of various density, shape and size were distributed randomly in the cytoplasm. Less melanin granules appear in the cell. Also, small drusen forms underneath BrM and basal lamina deposits forms in between the cell and BrM. (C) In AMD RPE, advanced mitochondrial alterations occur. Most mitochondria had severe disorganization of membranes that varied from focal to complete loss of cristae. Peroxisomes are clustered and aggregated in the cell. Large and soft drusen forms underneath the BrM.

FIGURE 3

Mitochondria changes in RPE senescence: PGAM5 dephosphorylates DRP-1 which promotes mitochondrial fission, which then inhibits the increase of ROS and ATP in RPE cellular senescence; H₂O₂ and CSE induce increased mitochondrial ROS and membrane potential, also induce decreased ATP level which cause RPE cellular senescence; PGC-1α is a master regulator of mitochondria biogenesis and could reduce ROS level which may inhibit RPE cellular senescence. PGAM5: phosphoglycerate mutase 5; DRP1: dynamin-related protein 1; H₂O₂: hydrogen peroxide; CSE: cigarette smoke extract; PGC-1α: peroxisome proliferator-activated receptor gamma coactivator-1α; ATP: adenosine triphosphate; ROS: reactive oxygen species; ΔΨm: mitochondrial membrane potential.

FIGURE 4

Mitochondria changes in RPE cell death induced by different stressors: A2E and blue light lead to fragmented mitochondria, imbalanced mitochondrial fusion/fission, decreased ATP level, increased ROS level and release of cytochrome C which then induce apoptosis; UV and menadione cause mitochondrial membrane damage, fragmented mitochondria, increased ROS level and release of cytochrome C which then induce apoptosis; H₂O₂, tBHP and NaIO₃ cause fragmented mitochondria and damaged mitochondrial network, and lead to necrosis. NaIO₃ also induces decreased mitochondrial membrane potential and increased ROS level, and leads to ferroptosis. High glucose induces mitochondrial membrane damage, fragmented mitochondria and cause ferroptosis; Auranofin causes decreased mitochondrial membrane potential, fragmented, vesiculated and damaged mitochondria, increased ROS level and decreased ATP level which lead to pyroptosis. A2E: N-retinylidene-N-retinyl-ethanolamine; UV: ultraviolet; H₂O₂: hydrogen peroxide; tBHP: tert-butyl hydroperoxide; NaIO₃: sodium iodate; ATP: adenosine triphosphate; ROS: reactive oxygen species; ΔΨm: mitochondrial membrane potential.