Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells.
Emiliano ZamponiNahuel ZamponiPinar CoskunGonzalo QuassolloAlfredo LorenzoSergio A CannasGustavo PiginoDante R ChialvoKatheleen GardinerJorge BusciglioPablo R HelgueraPublished in: Aging cell (2018)
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.
Keyphrases
- oxidative stress
- induced apoptosis
- dna damage
- diabetic rats
- ischemia reperfusion injury
- reactive oxygen species
- mouse model
- cell death
- endoplasmic reticulum stress
- stem cells
- wound healing
- physical activity
- signaling pathway
- heat shock
- transcription factor
- mesenchymal stem cells
- cancer therapy
- cell proliferation
- anti inflammatory