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Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells.

  • Author(s): Zamponi, Emiliano
  • Zamponi, Nahuel
  • Coskun, Pinar
  • Quassollo, Gonzalo
  • Lorenzo, Alfredo
  • Cannas, Sergio A
  • Pigino, Gustavo
  • Chialvo, Dante R
  • Gardiner, Katheleen
  • Busciglio, Jorge
  • Helguera, Pablo
  • et al.
Abstract

Mounting evidence implicates chronic oxidative stress as a critical driver of the aging process. Down syndrome (DS) is characterized by a complex phenotype, including early senescence. DS cells display increased levels of reactive oxygen species (ROS) and mitochondrial structural and metabolic dysfunction, which are counterbalanced by sustained Nrf2-mediated transcription of cellular antioxidant response elements (ARE). Here, we show that caspase 3/PKCδdependent activation of the Nrf2 pathway in DS and Dp16 (a mouse model of DS) cells is necessary to protect against chronic oxidative damage and to preserve cellular functionality. Mitochondria-targeted catalase (mCAT) significantly reduced oxidative stress, restored mitochondrial structure and function, normalized replicative and wound healing capacity, and rendered the Nrf2-mediated antioxidant response dispensable. These results highlight the critical role of Nrf2/ARE in the maintenance of DS cell homeostasis and validate mitochondrial-specific interventions as a key aspect of antioxidant and antiaging therapies.

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