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Association between ATP production and oxidative mtDNA damage through mitochondrial respiratory chain in the rat caecal ligation and puncture heart injury model

Introduction

Undisturbed generation of ATP, produced through NADH dehydrogenase in the respiratory chain, is required for the homeostasis of aerobic metabolism. In the case of a failing heart, excess production of reactive oxygen species (ROS) can cause an oxidative modification of mtDNA, such as 8-oxo-dGTP, which can lead to defects in DNA replication. On the other hand, free radical scavengers, such as polyethyleneglycole catalase (PEG-CAT), have been considered with improvement of defection in DNA replication through hydrolyzing 8-oxo-dG by the human functional homologue of the MutT protein (hMTH1 for mutt homologue 1; MTH-1) in the rat caecal ligation and puncture (CLP) model. However, associations between oxidative mtDNA damage and ATP production have not been well isolated clearly in the rat CLP heart injury model.

Methods

Sepsis was induced by CLP. Adult male Sprague–Dawley rats (n = 20) after 4 hours of CLP were administrated with or without free radical scavengers (H2O2 scavenger: PEG-CAT). We measured cardiomyocyte generation of MTH-1 by RT-PCR, NAD/NADH ratio, ATP production and 8-oxo-dG by HPLC with or without inhibition of ROS by PEG-CAT in the rat CLP heart injury model.

Results

Both the NAD/NADH ratio and ATP production level of the PEG-CAT(+) group were significantly increased compared with the PEG-CAT(-) group (P < 0.05), but these level had not normalized. The 8-oxo-dG level of the PEG-CAT(-) group were increased compared with the PEG-CAT(+) group (P < 0.05). The mRNA of MTH-1 level of PEG-CAT(+) group was significantly higher compared with the PEG-CAT(-) group (P < 0.05). See Table 1.

Table 1 Effects of PEG-CAT on myocarditis

Conclusion

ATP production of the mitochondria may be inhibited by mtDNA damage of ROS through the respiratory chain.

References

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Hirata, J., Oya, M., Kotani, J. et al. Association between ATP production and oxidative mtDNA damage through mitochondrial respiratory chain in the rat caecal ligation and puncture heart injury model. Crit Care 12, P387 (2008). https://doi.org/10.1186/cc6608

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Keywords

  • Reactive Oxygen Species
  • Respiratory Chain
  • Free Radical Scavenger
  • Mitochondrial Respiratory Chain
  • NADH Dehydrogenase