Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress

These results indicate that mtDNA is a critical cellular target for reactive oxygen species

F. M. Yakes; B. Van Houten


Scholarcy highlights

  • A significant amount of reactive oxygen species is generated during mitochondrial oxidative phosphorylation
  • The present study has revealed that mtDNA is more sensitive than nuclear DNA to hydrogen peroxide-induced damage, and protracted treatment leads to persistent mtDNA damage and loss of mitochondrial function
  • In this study we found that H2O2-induced mtDNA damage occurred rapidly and was more extensive than damage to a 17.7-kb fragment 5Ј to the ␤-globin gene; a 60-min exposure to H2O2 resulted in mtDNA damage that was not repaired, whereas damage to the ␤-globin fragment was completely removed within 1.5 hr; a 15-min exposure to H2O2 resulted in DNA damage that was efficiently repaired in both the ␤-globin fragment and mtDNA; and the persistence of mtDNA damage correlated with the loss of mitochondrial function, the induction of WAF1͞CIPI, a permanent growth arrest, and apoptosis
  • Damage could be due to several factors, including: the absence of complex chromatin organization, which may serve as a protective barrier against ROS; alterations in DNA repair activity; the presence of localized metal ions that may function as catalysts in the generation of ROS; and the stimulation of secondary ROS reactions due to damage to the electron transport chain andor through lipid peroxidation
  • Because mtDNA is deficient in histones, and lacks the complexity associated with nuclear DNA, mtDNA may be more prone to attack by oxidants
  • Because H2O2 is unreactive unless transition metals or superoxide radicals are present, it is possible that metal ions, such as Fe2ϩ, may be limiting in the nucleus and an increase in H2O2 may not necessarily show increasing amounts of DNA damage
  • The increased expression of the cyclin-dependent kinase inhibitor WAF1͞CIP1 and subsequent induction of a permanent growth arrest following a 60-min exposure to hydrogen peroxide correlated with those cells in which mtDNA repair was undetectable

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