Introduction

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in developed countries. This multifactorial disease involves complex genetic and environmental factors whose effects accelerate with age1,2. AMD affects 30% of individuals 75–85 years of age, with a global estimate of 128 million cases in 2020 and 288 million cases by 2040, a consequence of the world’s increasing elderly population3,4. The two forms of AMD include “wet” and “dry”, with wet AMD caused by the abnormal growth of blood vessels into the retina. While wet AMD is less common, it has a number of effective therapies to halt or prevent vision loss5. Dry AMD is the most common form of the disease, accounting for approximately 85% of all AMD cases6. Vision loss associated with dry AMD is caused by the death of retinal pigment epithelium (RPE) and photoreceptors. RPE are essential for maintaining a healthy retina as they are responsible for key functions, such as the transport of nutrients to photoreceptors and the directed secretion of growth factors7. Currently, there are no effective treatments for dry AMD, due to our incomplete understanding of the cellular events causing disease pathology. Thus, there remains an urgent need to identify the underlying mechanisms causing AMD in order to successfully develop therapeutic interventions.

One of the prevailing hypotheses is that RPE mitochondrial defects drive AMD pathology8. This hypothesis is supported by numerous studies in human retina from eye bank donors. Analysis of electron microscopy images found donors with AMD had significantly fewer mitochondrial number, reduced surface area, and an altered cristae morphology9. Additionally, proteomic studies of human RPE tissue found an altered mitochondrial proteome, with multiple proteins in the electron transport chain decreasing in AMD RPE10,11. There are also reports of increased mitochondrial DNA damage with progression of AMD severity12,13. Consistent with the mitochondrial defects observed in tissue, cultures of human primary RPE showed significantly decreased mitochondrial function in RPE from donors with AMD14,46. Additional compounds designed to protect mitochondria from oxidative damage (N-acetyl-L-Cysteine; NAC), remove damaged mitochondria via increased autophagy (rapamycin), upregulate mitochondrial biogenesis (pyrroloquinoline; PQQ), or improve oxidative phosphorylation (nicotinamide mononucleotide, NMN) have been investigated in our lab47. We found that RPE from AMD donors responded to the drugs as detected by the increase in mitochondrial function. In contrast, RPE from donors without AMD did not respond to the drugs. These results are consistent with the idea that mitochondrial dysfunction in the diseased cells can be ameliorated by treatments that target mitochondrial defects. Our study supports the idea that mitochondrial defects drive AMD, and targeting pathways of mitochondrial homeostasis may be a viable treatment option.

This study uncovers potential mechanisms leading to mitochondrial damage and dysfunction associated with AMD that may initiate the metabolic crisis in the retina. We observed disease-specific differences under basal conditions and in response to two mitochondrial stressors, FCCP and CoCl2. The AMD-associated changes in mitochondrial proteins reported in this study could lead to the buildup of damaged and dysfunctional mitochondria that begins to disrupt the delicate retinal ecosystem and lead to the eventual death of RPE and photoreceptors in AMD. Experiments using different stressors and analytical methods may further identify mechanisms that explain these AMD-associated changes in mitochondrial homeostasis, providing new therapeutic targets to treat AMD.