DNA-PKcs promotes cardiac ischemia reperfusion injury through mitigating BI-1-governed mitochondrial homeostasis

Hao Zhou, Sam Toan, Pingjun Zhu, Jin Wang, Jun Ren, Yingmei Zhang

Research output: Contribution to journalArticlepeer-review

63 Scopus citations


DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a novel inducer to promote mitochondrial apoptosis and suppress tumor growth in a variety of cells although its role in cardiovascular diseases remains obscure. This study was designed to examine the role of DNA-PKcs in cardiac ischemia reperfusion (IR) injury and mitochondrial damage. Cardiomyocyte-specific DNA-PKcs knockout (DNA-PKcsCKO) mice were subjected to IR prior to assessment of myocardial function and mitochondrial apoptosis. Our data revealed that IR challenge, hypoxia-reoxygenation (HR) or H2O2-activated DNA-PKcs through post-transcriptional phosphorylation in murine hearts or cardiomyocytes. Mice deficient in DNA-PKcs in cardiomyocytes were protected against cardiomyocyte death, infarct area expansion and cardiac dysfunction. DNA-PKcs ablation countered IR- or HR-induced oxidative stress, mPTP opening, mitochondrial fission, mitophagy failure and Bax-mediated mitochondrial apoptosis, possibly through suppression of Bax inhibitor-1 (BI-1) activity. A direct association between DNA-PKcs and BI-1 was noted where DNA-PKcs had little effect on BI-1 transcription but interacted with BI-1 to promote its degradation. Loss of DNA-PKcs stabilized BI-1, thus offering resistance of mitochondria and cardiomyocytes against IR insult. Moreover, DNA-PKcs ablation-induced beneficial cardioprotection against IR injury was mitigated by concurrent knockout of BI-1. Double deletion of DNA-PKcs and BI-1 failed to exert protection against global IR injury and mitochondrial damage, confirming a permissive role of BI-1 in DNA-PKcs deletion-elicited cardioprotection against IR injury. DNA-PKcs serves as a novel causative factor for mitochondrial damage via suppression of BI-1, en route to the onset and development of cardiac IR injury.

Original languageEnglish (US)
Article number11
JournalBasic research in cardiology
Issue number2
StatePublished - Mar 1 2020

Bibliographical note

Funding Information:
This work was supported in part by National Key R&D Program of China (2017YFA0506000), China Postdoctoral Science Foundation (2019TQ0128) and the NSFC (81900252, 81770261, 81870249, 81900254 and 91749128).

Publisher Copyright:
© 2020, Springer-Verlag GmbH Germany, part of Springer Nature.


  • BI-1
  • Dna-pkcs. apoptosis
  • IR injury
  • Mitochondria
  • Mitochondria, Heart/enzymology
  • Signal Transduction
  • Humans
  • Mice, Inbred C57BL
  • Cells, Cultured
  • Membrane Proteins/genetics
  • Homeostasis
  • Male
  • Myocytes, Cardiac/enzymology
  • Myocardial Infarction/enzymology
  • Mice, Knockout
  • DNA-Activated Protein Kinase/deficiency
  • Animals
  • DNA-Binding Proteins/deficiency
  • Proteolysis
  • Myocardial Reperfusion Injury/enzymology
  • Protein Stability
  • Apoptosis
  • Disease Models, Animal

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Journal Article


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