Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

ZAMPONI, EMILIANO; QUASSOLLO, GONZALO; PIGINO, GUSTAVO; COSKUN, PINAR; BUSCIGLIO, JORGE; CANNAS, SERGIO A.; ZAMPONI, NAHUEL; ZAMPONI, NAHUEL; GARDINER, KATHELEEN; LORENZO, ALFREDO; LORENZO, ALFREDO; ZAMPONI, EMILIANO; CHIALVO, DANTE R.; CHIALVO, DANTE R.; QUASSOLLO, GONZALO; HELGUERA, PABLO; HELGUERA, PABLO; COSKUN, PINAR; PIGINO, GUSTAVO; CANNAS, SERGIO A.; BUSCIGLIO, JORGE; GARDINER, KATHELEEN

AGING CELL

WILEY-BLACKWELL PUBLISHING, INC

Año: 2018 vol. 17

1474-9718

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.