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Mitochondrial H2O2 release does not directly cause damage to chromosomal DNA

Author

Listed:
  • Daan M. K. Soest

    (University Medical Center Utrecht)

  • Paulien E. Polderman

    (University Medical Center Utrecht)

  • Wytze T. F. Toom

    (University Medical Center Utrecht)

  • Janneke P. Keijer

    (University Medical Center Utrecht)

  • Markus J. Roosmalen

    (Princess Máxima Center for Pediatric Oncology)

  • Tim M. F. Leyten

    (University Medical Center Utrecht)

  • Johannes Lehmann

    (University Medical Center Utrecht)

  • Susan Zwakenberg

    (University Medical Center Utrecht)

  • Sasha Henau

    (University Medical Center Utrecht)

  • Ruben Boxtel

    (Princess Máxima Center for Pediatric Oncology
    Oncode Institute)

  • Boudewijn M. T. Burgering

    (University Medical Center Utrecht
    Oncode Institute)

  • Tobias B. Dansen

    (University Medical Center Utrecht)

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 H2O2 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 H2O2. Nuclear H2O2 gives rise to DNA damage and mutations and a subsequent p53 dependent cell cycle arrest. Mitochondrial H2O2 release shows none of these effects, even at levels that are orders of magnitude higher than what mitochondria normally produce. We conclude that H2O2 released from mitochondria is unlikely to directly damage nuclear genomic DNA, limiting its contribution to oncogenic transformation and aging.

Suggested Citation

  • Daan M. K. Soest & Paulien E. Polderman & Wytze T. F. Toom & Janneke P. Keijer & Markus J. Roosmalen & Tim M. F. Leyten & Johannes Lehmann & Susan Zwakenberg & Sasha Henau & Ruben Boxtel & Boudewijn M, 2024. "Mitochondrial H2O2 release does not directly cause damage to chromosomal DNA," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47008-x
    DOI: 10.1038/s41467-024-47008-x
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