28 March 2024 | Daan M. K. van Soest, Paulien E. Polderman, Wytze T. F. den Toom, Janneke P. Keijer, Markus J. van Roosmalen, Tim M. F. Leyten, Johannes Lehmann, Susan Zwakenberg, Sasha De Henau, Ruben van Boxtel, Boudewijn M. T. Burgering, Tobias B. Dansen
This study investigates the effects of hydrogen peroxide (H₂O₂) released by mitochondria on nuclear DNA damage. Using a chemogenetic approach, researchers localized H₂O₂ production to either the nucleosomes or the mitochondrial membrane. They found that H₂O₂ produced at the nucleosomes caused DNA mutations, strand breaks, and activation of the DNA damage response (DDR), leading to p53-dependent cell cycle arrest and senescence. In contrast, H₂O₂ released from mitochondria did not induce these effects, even at levels much higher than those normally produced by mitochondria. The study concludes that mitochondrial H₂O₂ release is unlikely to directly damage nuclear genomic DNA, limiting its contribution to oncogenic transformation and aging. The findings suggest that ROS-inducing agents may be effective in inducing cell cycle arrest and senescence, but they should be targeted to the nucleus to maximize their therapeutic potential.This study investigates the effects of hydrogen peroxide (H₂O₂) released by mitochondria on nuclear DNA damage. Using a chemogenetic approach, researchers localized H₂O₂ production to either the nucleosomes or the mitochondrial membrane. They found that H₂O₂ produced at the nucleosomes caused DNA mutations, strand breaks, and activation of the DNA damage response (DDR), leading to p53-dependent cell cycle arrest and senescence. In contrast, H₂O₂ released from mitochondria did not induce these effects, even at levels much higher than those normally produced by mitochondria. The study concludes that mitochondrial H₂O₂ release is unlikely to directly damage nuclear genomic DNA, limiting its contribution to oncogenic transformation and aging. The findings suggest that ROS-inducing agents may be effective in inducing cell cycle arrest and senescence, but they should be targeted to the nucleus to maximize their therapeutic potential.