1. Mitochondrial H2O2 release does not directly cause damage to chromosomal DNA.
- Author
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van Soest, Daan M. K., Polderman, Paulien E., den Toom, Wytze T. F., Keijer, Janneke P., van Roosmalen, Markus J., Leyten, Tim M. F., Lehmann, Johannes, Zwakenberg, Susan, De Henau, Sasha, van Boxtel, Ruben, Burgering, Boudewijn M. T., and Dansen, Tobias B.
- Subjects
NUCLEAR DNA ,MITOCHONDRIA ,CELL cycle ,REACTIVE oxygen species ,DNA damage - Abstract
Reactive Oxygen Species (ROS) derived from mitochondrial respiration are frequently cited as a major source of chromosomal DNA mutations that contribute to cancer development and aging. However, experimental evidence showing that ROS released by mitochondria can directly damage nuclear DNA is largely lacking. In this study, we investigated the effects of H
2 O2 released by mitochondria or produced at the nucleosomes using a titratable chemogenetic approach. This enabled us to precisely investigate to what extent DNA damage occurs downstream of near- and supraphysiological amounts of localized H2 O2 . Nuclear H2 O2 gives rise to DNA damage and mutations and a subsequent p53 dependent cell cycle arrest. Mitochondrial H2 O2 release shows none of these effects, even at levels that are orders of magnitude higher than what mitochondria normally produce. We conclude that H2 O2 released from mitochondria is unlikely to directly damage nuclear genomic DNA, limiting its contribution to oncogenic transformation and aging. Nuclear DNA damage downstream of mitochondrial ROS is often cited to contribute to cancer initiation and aging. However, here the authors show that although H2 O2 induces DNA mutations when produced near DNA, it does not when released by mitochondria. [ABSTRACT FROM AUTHOR]- Published
- 2024
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