Oxidative stress induces mitochondrial dysfunction and a protective unfolded protein response in RPE cells

Marisol Cano, Lei Wang, Jun Wan, Bradley P. Barnett, Katayoon Katayo Baradaran Ebrahimi, Jiang Qian, James T. Handa

Research output: Contribution to journalArticlepeer-review

57 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1-14
Number of pages14
JournalFree Radical Biology and Medicine
StatePublished - Apr 2014


  • Aging-related disease
  • ER stress
  • Epithelial-mesenchymal transition
  • Free radicals
  • Mitochondria
  • Oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)


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