Oxidative stress induces mitochondrial dysfunction and a protective unfolded protein response in RPE cells |
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| Affiliation: | 3. VA Nebraska-Western Iowa Health Care System, Department of Research Service, Omaha, Nebraska 68105;4. Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198;5. Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198;1. Department of Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9057, USA;2. Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA;1. Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA;2. Department of Ophthalmology, Tulane University, New Orleans, LA 70118, USA;1. Department of Ophthalmology and Visual Neurosciences and Graduate Program in Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA;2. Ophthalmology, Vision, and Anatomical Sciences, Wayne State University, Detroit, MI, USA |
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| Abstract: | How cells degenerate from oxidative stress in aging-related disease is incompletely understood. This study’s intent was to identify key cytoprotective pathways activated by oxidative stress and determine the extent of their protection. Using an unbiased strategy with microarray analysis, we found that retinal pigmented epithelial (RPE) cells treated with cigarette smoke extract (CSE) had overrepresented genes involved in the antioxidant and unfolded protein response (UPR). Differentially expressed antioxidant genes were predominantly located in the cytoplasm, with no induction of genes that neutralize superoxide and H2O2 in the mitochondria, resulting in accumulation of superoxide and decreased ATP production. Simultaneously, CSE induced the UPR sensors IRE1α, p-PERK, and ATP6, including CHOP, which was cytoprotective because CHOP knockdown decreased cell viability. In mice given intravitreal CSE, the RPE had increased IRE1α and decreased ATP and developed epithelial–mesenchymal transition, as suggested by decreased LRAT abundance, altered ZO-1 immunolabeling, and dysmorphic cell shape. Mildly degenerated RPE from early age-related macular degeneration (AMD) samples had prominent IRE1α, but minimal mitochondrial TOM20 immunolabeling. Although oxidative stress is thought to induce an antioxidant response with cooperation between the mitochondria and the ER, herein we show that mitochondria become impaired sufficiently to induce epithelial–mesenchymal transition despite a protective UPR. With similar responses in early AMD samples, these results suggest that mitochondria are vulnerable to oxidative stress despite a protective UPR during the early phases of aging-related disease. |
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| Keywords: | Aging-related disease Epithelial–mesenchymal transition ER stress Mitochondria Oxidative stress Free radicals |
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