Mitochondrial oxidative stress in the retinal pigment epithelium (RPE) led to metabolic dysfunction in both the RPE and retinal photoreceptors

Abstract

Age-related macular degeneration (AMD) is the leading cause of vision loss in the western world. Recent evidence suggests that RPE and photoreceptors have an interconnected metabolism and that mitochondrial damage in RPE is a trigger for degeneration in both RPE and photoreceptors in AMD. To test this hypothesis, this study was designed to induce mitochondrial damage in RPE in mice to determine whether this is sufficient to cause RPE and photoreceptor damage characteristic of AMD. In this study, we conditionally deleted the gene encoding the mitochondrial antioxidant enzyme, manganese superoxide dismutase (MnSOD encoded by Sod2 ) in the retinal pigment epithelium (RPE) of albino BALB/cJ mice. VMD2-Cre;Sod2 flox/flox BALB/cJ mice were housed in either 12-h dark, 12-h 200 lux white lighting (normal light), or 12-h dark, 12-h <10 lux red lighting (dim light). Electroretinography (ERG) and spectral-domain optical coherence tomography (SD-OCT) were performed to assess retinal function and morphology. Immunofluorescence was used to examine protein expression; quantitative RT-PCR was used to measure gene expression. Sod2 knockout (KO) mice had reduced RPE function with age and increased oxidative stress compared to wild type (WT) controls as expected by the cell-specific deletion of Sod2. This was associated with alterations in RPE morphology and the structure and function of RPE mitochondria. In addition, data show a compensatory increase in RPE glycolytic metabolism. The metabolic shift in RPE correlated with severe disruption of photoreceptor mitochondria including a reduction in TOMM20 expression, mitochondrial fragmentation, and reduced COXIII/β-actin levels. These findings demonstrate that mitochondrial oxidative stress can lead to RPE dysfunction and metabolic reprogramming of RPE. Secondary to these changes, photoreceptors also undergo metabolic stress with increased mitochondrial damage. These data are consistent with the hypothesis of a linked metabolism between RPE and photoreceptors and suggest a mechanism of retinal degeneration in dry AMD.

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

“…These alterations in Bruch’s membrane structure alter physiological conductivity and therefore impede a correct transport of oxygen or nutrients from the choroidal network to the RPE cells [35-38], resulting in a condition of hypoxia [39] and starvation. In addition, lifestyle habits, like smoking or maintaining a high-fat diet, both risk factors for AMD [7, 40], add oxidative stress to the retina [41, 42], and in particular to the mitochondria of RPE cells and photoreceptors [11]. With age, and more pronounced in AMD patients, mitochondrial damage is augmented [10, 43], thus leading to energy misbalance in the RPE cells.…”

“…Of the proteins differentially expressed in RPE cells from AMD donors and healthy controls, many are mitochondrial proteins [10]. Moreover, it has been shown in a mouse model that conditionally-induced mitochondrial damage in RPE cells leads to cell metabolic reprogramming and photoreceptors malfunction [11].…”

The Emerging Role of Senescence in Ocular Disease

“…A strong link between mitochondrial metabolism and the senescent state has been proposed [162]. Acute oxidative stress can cause increased ROS production which is linked to mitochondrial oxidative damage, a reduction in mitochondrial copy number, and decreased mitochondrial respiration and ATP production in RPE cells [39,[163][164][165]. Repeated exposure stress can also induce ROS which in turn can induce and regulate cellular senescence and can cause major changes in the metabolome [166].…”

Metabolic features of mouse and human retinas: rods vs. cones, macula vs. periphery, retina vs. RPE

“…Inhibition of RPE mitochondrial metabolism is sufficient to cause AMD-like retinal degeneration in mice 18,19,20 . Conversely, impairment of photoreceptor metabolism also influences RPE health 21 . Accumulating evidence supports the concept that photoreceptors and RPE form an inter-dependent metabolic ecosystem 21,22,23,24,25 .…”

“…Conversely, impairment of photoreceptor metabolism also influences RPE health 21 . Accumulating evidence supports the concept that photoreceptors and RPE form an inter-dependent metabolic ecosystem 21,22,23,24,25 . Photoreceptors shed lipid-rich outer segment discs and export lactate due to the Warburg effect; the RPE converts the outer segment discs into ketone bodies to fuel photoreceptors and it utilizes lactate to preserve glucose for photoreceptors 23,26 .…”