Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

Aging Cell
Emiliano ZamponiPablo Helguera

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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Citations

Mar 5, 2019·Developmental Neurobiology·E Zamponi, P R Helguera
Nov 19, 2019·Oxidative Medicine and Cellular Longevity·Lian-Jiu SuZhi-Yong Peng
Jul 16, 2019·Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association·Peter StenvinkelPaul G Shiels
Aug 7, 2020·Antioxidants·Noemí Rueda Revilla, Carmen Martínez-Cué
Sep 22, 2019·International Journal of Molecular Sciences·David L Newman, Stephen L Gregory
Jul 21, 2020·Oxidative Medicine and Cellular Longevity·Ningning TaoJingjing Liu
Feb 3, 2021·Proceedings of the National Academy of Sciences of the United States of America·Sunyoung HwangEduardo M Torres
Mar 7, 2021·Biomolecules·Chiara Lanzillotta, Fabio Di Domenico
Nov 10, 2021·F1000Research·Ayati SharmaAnna Delprato
Jun 19, 2021·Frontiers in Immunology·Genni Enza MarcovecchioAnna Villa
Jun 20, 2021·Journal of Cellular and Molecular Medicine·Yang LiuZhenbing Chen
Jun 16, 2021·Free Radical Biology & Medicine·Colin C AndersonJames R Roede

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Methods Mentioned

BETA
transgenic
biosensor
nuclear translocation
Protein Assay
PCR

Software Mentioned

R
mCAT

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