dATP causes specific release of cytochrome C from mitochondria.
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.
Yang
J C
JC
Department of Molecular Biosciences, University of California, Davis 95616, USA.
Cortopassi
G A
GA
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D003574:Cytochrome c Group / Q000378:metabolism*; D003838:Deoxyadenine Nucleotides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008930:Mitochondria, Liver / Q000201:enzymology*
D003574:Cytochrome c Group; D003838:Deoxyadenine Nucleotides; D000255:Adenosine Triphosphate