dATP causes specific release of cytochrome C from mitochondria

JC Yang, GA Cortopassi - Biochemical and biophysical research …, 1998 - Elsevier
JC Yang, GA Cortopassi
Biochemical and biophysical research communications, 1998Elsevier
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 …
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.
Elsevier