Collectively, the data indicate that mtDNA is preferentially damaged with AMD progression. These results suggest a potential link between mt dysfunction due to increased mtDNA lesions and AMD.

The results are consistent with the hypothesis that mitochondrial dysfunction is associated with AMD and further suggest specific pathophysiological mechanisms involving altered mitochondrial translation, import of nuclear-encoded proteins, and ATP synthase activity.

PURPOSE-To examine changes of select reduction-oxidation (redox) sensitive proteins from human donor retinal pigment epithelium (RPE) at four stages of age-related macular degeneration (AMD). DESIGN-Experimental study.METHODS-Human donor eyes were obtained from the Minnesota Lions Eye Bank and graded using the Minnesota Grading System (MGS) into four stages that correspond to stages defined by the age-related eye disease study (AREDS). Protein content in RPE homogenates was measured using Western immunoblotting with protein-specific antibodies.RESULTS-The content of several antioxidant enzymes and specific proteins that facilitate refolding or degradation of oxidatively damaged proteins increased significantly in MGS stage 3. These proteins are involved in the primary (copper-zinc superoxide dismutase [CuZnSOD], manganese superoxide dismutase [MnSOD], and catalase) and secondary (heat shock protein [HSP] 27, HSP 90, and proteasome) defense against oxidative damage. Additionally, the insulin prosurvival receptor exhibited disease-related upregulation.CONCLUSIONS-The pattern of protein changes identified in human donor tissue graded using the MGS support the role of oxidative mechanisms in the pathogenesis and progression of AMD. The MGS uses nearly identical clinical definitions and grading criteria of AMD that are used in the AREDS, so our results apply to clinical and epidemiologic studies using similar definitions. Results from our protein analysis of human donor tissue helps to explain altered oxidative stress regulation and cell-survival pathways that occur in progressive stages of AMD.Age-related macular degeneration (amd) is the leading cause of blindness in developed countries 1-9 . The number of affected individuals in the United States alone is expected to increase nearly twofold, to approximately three million by the year 2020. 10 Fortunately, therapeutic options are improving. The use of antioxidant vitamins has been shown to delay disease progression at an intermediate stage, 11 and rapid innovation in the use of antiangiogenic therapies has resulted in new clinical methods to treat the exudative phase of AMD. 12-18 However, developing new treatment and prevention strategies targeting earlier stages of the disease requires a better understanding of the underlying disease mechanisms.Findings from the Age-Related Eye Disease Study (AREDS) clearly support the hypothesis that oxidative mechanisms play a significant role in the progression of AMD. Although several studies have shown that the intake of antioxidant-rich foods lowers the risk of AMD, 19-24 others have not supported this conclusion. 25-27 Cigarette smoking, a pro-oxidant, NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript significantly increases the risk of AMD, and this association is well supported in numerous, well-designed studies. 28-35The retinal pigment epithelium (RPE) is subject to a particularly high level of oxidative stress because of locally elevated oxygen tension, high polyunsaturated lipid con...