Age-related macular degeneration: etiology, pathogenesis, and therapeutic strategies.

Molecular pathology of age-related macular degeneration

Oxidative stress-induced mitochondrial DNA damage in human retinal pigment epithelial cells: a possible mechanism for RPE aging and age-related macular degeneration.

Background— Coronary atherosclerotic disease remains the leading cause of death in the Western world. Although the exact sequence of events in this process is controversial, reactive oxygen and nitrogen species (RS) likely play an important role in vascular cell dysfunction and atherogenesis. Oxidative damage to the mitochondrial genome with resultant mitochondrial dysfunction is an important consequence of increased intracellular RS. Methods and Results— We examined the contribution of mitochondrial oxidant generation and DNA damage to the progression of atherosclerotic lesions in human arterial specimens and atherosclerosis-prone mice. Mitochondrial DNA damage not only correlated with the extent of atherosclerosis in human specimens and aortas from apolipoprotein E−/− mice but also preceded atherogenesis in young apolipoprotein E−/− mice. Apolipoprotein E−/− mice deficient in manganese superoxide dismutase, a mitochondrial antioxidant enzyme, exhibited early increases in mitochondrial DNA damage and a p...

Mitochondrial Integrity and Function in Atherogenesis

The mechanisms by which reactive species (RS) participate in the development of atherosclerosis remain incompletely understood. The present study was designed to test the hypothesis that RS produced in the vascular environment cause mitochondrial damage and dysfunction in vitro and, thus, may contribute to the initiating events of atherogenesis. DNA damage was assessed in vascular cells exposed to superoxide, hydrogen peroxide, nitric oxide, and peroxynitrite. In both vascular endothelial and smooth muscle cells, the mitochondrial DNA (mtDNA) was preferentially damaged relative to the transcriptionally inactive nuclear beta-globin gene. Similarly, a dose-dependent decrease in mtDNA-encoded mRNA transcripts was associated with RS treatment. Mitochondrial protein synthesis was also inhibited in a dose-dependent manner by ONOO(-), resulting in decreased cellular ATP levels and mitochondrial redox function. Overall, endothelial cells were more sensitive to RS-mediated damage than were smooth muscle cells. Together, these data link RS-mediated mtDNA damage, altered gene expression, and mitochondrial dysfunction in cell culture and reveal how RS may mediate vascular cell dysfunction in the setting of atherogenesis.

B F Godley

Papers

Hydrogen peroxide causes significant mitochondrial DNA damage in human RPE cells.