DNase activation by hypoxia-acidosis parallels but is independent of programmed cell death

John W. Thompson, Regina M. Graham, Keith A. Webster

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Aims: Hypoxia, acidosis and programmed cell death are each hallmarks of acute myocardial infarction (AMI). We previously described a death pathway of cardiac myocytes mediated by hypoxia-acidosis that was characterized by activation of the Bcl2-family protein Bnip3 and programmed necrosis. The pathway included extensive DNA fragmentation that was sensitive to inhibition of the mitochondrial permeability transition pore (mPTP) and calpain inhibitors, but not caspase inhibitors. We did not identify the DNases responsible for DNA cleavage. Main methods: Neonatal rat cardiomyocytes were subjected to hypoxia with and without concurrent acidosis, and the cellular localization of apoptosis-inducing factor (AIF), DNase II and caspase-dependent DNase (CAD) were determined. Key findings: Here we report the occurrence of biphasic pH-dependent translocations of AIF and DNase II but no change in CAD or its inhibitor ICAD. AIF co-localized with the mitochondria under aerobic and hypoxia-neutral conditions but translocated to the nucleus at pH ~ 6.7 coincident with a decrease of the mitochondrial membrane potential. DNase II co-localized with lysosomes under normoxia and hypoxia-neutral conditions, and translocated to the nucleus at pH ~ 6.1 coincident with the appearance of single strand DNA cuts. Inhibition of the mPTP pore with BH4-TAT peptide, calpain inhibition with PD150606, or knockdown (KD) of Bnip3 failed to prevent nuclear translocation of these DNase although Bnip3 KD blocked mitochondrial fission. Significance: These results suggest that caspase-independent DNA fragmentation is precisely regulated and occurs in parallel but independently from programmed necrosis mediated by hypoxia-acidosis.

Original languageEnglish (US)
Pages (from-to)223-229
Number of pages7
JournalLife Sciences
Volume91
Issue number7-8
DOIs
StatePublished - Sep 17 2012

Keywords

  • Apoptosis inducing factor
  • Bnip3
  • Calpains
  • Cardiac myocyte
  • DNase II
  • Hypoxia
  • Ischemia
  • Mitochondrial fission

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint

Dive into the research topics of 'DNase activation by hypoxia-acidosis parallels but is independent of programmed cell death'. Together they form a unique fingerprint.

Cite this