dATP causes specific release of cytochrome c from mitochondria

Joy C. Yang, Gino A Cortopassi

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

The induction of the Mitochondrial Permeability Transition (MPT) has recently been associated with the release of apoptogenic cytochrome c, which could come about in a swelling-dependent or swelling-independent manner. We observed that canonical inducers of MPT (Ca2+, t-butyl hydroperoxide, atractyloside) induce a swelling-dependent release of cytochrome c, and that osmotic support of mitochondria with PEG-1000 abolishes mitochondrial swelling, protein release, and cytochrome c release by these inducers. By contrast, it was observed that dATP is a potent inducer that caused release of cytochrome c in a swelling independent manner, i.e. even in the presence of osmotic support by PEG-1000; in addition this release of cytochrome c is inhibitable by cyclosporin A. The dATP-dependent and swelling-independent release of cytochrome c from mitochondria is not inhibitable by the protease inhibitor z-VAD, suggesting that it is not mediated by upstream caspases. This is the first report to our knowledge that a chemical compound may directly cause release of cytochrome c from mitochondria, and could explain the toxicity of dATP in the context of the genetic immunodeficiency diseases Adenosine Deaminase deficiency and Purine Nucleotide Phosphorylase deficiency.

Original languageEnglish (US)
Pages (from-to)454-457
Number of pages4
JournalBiochemical and Biophysical Research Communications
Volume250
Issue number2
DOIs
StatePublished - Sep 18 1998

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

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