Mitochondrial Dysfunction in Retinal Pigment Epithelium with Age-related Macular Degeneration

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Mitochondrial Dysfunction in Retinal Pigment Epithelium with Age-related Macular Degeneration

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2022-04

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Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. The dry form of AMD, also known as atrophic AMD, is characterized by the death of retinal pigment epithelium (RPE) and photoreceptors. Currently, there are no treatments for this form of the disease due in part to our incomplete understanding of the mechanism causing AMD. Strong experimental evidence from studies of human donors with AMD supports the emerging hypothesis that defects in RPE mitochondria drives AMD pathology. These studies, using different experimental methods, have shown (i) disrupted RPE mitochondrial architecture and decreased mitochondrial number and mass, (ii) altered content of multiple mitochondrial proteins, (iii) increased mitochondrial DNA (mtDNA) damage that correlates with disease severity, and (iv) defects in bioenergetics for primary RPE cultures from AMD donors.The recent generation of human primary RPE cell cultures has provided a unique and excited opportunity to investigate disease mechanisms in the RPE from diseased and age-matched controls. Used extensively in this thesis, primary RPE cultures from human donors graded for disease severity allowed for the testing of our central hypothesis: Damaged and dysfunctional mitochondria accumulate in the RPE of AMD donors due to defects in one or more pathways of mitochondrial homeostasis. The results of this thesis show that mitochondrial dysfunction is maintained in the primary RPE from AMD donors, a finding produced in two separate groups of donors (Chapter 2 and Chapter 5). Investigation into the pathways of mitochondrial homeostasis in primary RPE uncovered AMD-specific responses to FCCP and CoCl2 induced stress (Chapter 3 and Chapter 4). These results suggest that the accumulation of damaged and dysfunctional mitochondria in AMD RPE may stem from a combinatorial effect of defective regulation or utilization of pathways maintaining mitochondrial homeostasis. Data from this thesis supports the hypothesis that damaged mitochondria accumulate in the RPE of AMD donors due to defects in mitochondrial homeostasis. Targeting the mitochondria and the pathways that regulate mitochondrial homeostasis may be a valid treatment strategy for AMD.

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University of Minnesota Ph.D. dissertation. 2022. Major: Biochemistry, Molecular Bio, and Biophysics. Advisor: Deborah Ferrington. 1 computer file (PDF); 190 pages.

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Fisher, Cody. (2022). Mitochondrial Dysfunction in Retinal Pigment Epithelium with Age-related Macular Degeneration. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/241385.

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