Open AccessNrf2 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
Publication year - 2018
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12812
Subject(s) - oxidative stress , mitochondrion , reactive oxygen species , biology , microbiology and biotechnology , oxidative phosphorylation , catalase , antioxidant , phenotype , mitochondrial ros , homeostasis , senescence , transcription factor , biochemistry , gene
Summary 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.