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1 Center for Free Radical Biology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
* To whom correspondence should be addressed. E-mail: darley{at}path.uab.edu.
The mitochondrial permeability transition pore (PTP) is a membrane protein complex assembled and opened in response to Ca2+ and oxidants such as peroxynitrite (ONOO-). Opening of the PTP is mechanistically linked to the release of cytochrome c, which participates in downstream apoptotic signaling. However, the molecular basis of the synergistic interactions between oxidants and Ca2+ in promoting the PTP is poorly understood and are addressed in the present study. In isolated rat liver mitochondria it was found that the timing of the exposure of the isolated rat liver mitochondria to Ca2+ was a critical factor in determining the impact of ONOO- on PTP. Specifically, addition of Ca2+ alone, or ONOO- then Ca2+, elicited similar low levels of PTP opening whereas ONOO- alone was ineffective. In contrast, addition of Ca2+ then ONOO- induced extensive PTP opening and cytochrome c release. Interestingly, Cu/Zn superoxide dismutase enhanced pore opening through a mechanism independent of its catalytic activity. These data are consistent with a model in which Ca2+ reveals a molecular target that is now reactive with ONOO-. As a test of this hypothesis tyrosine nitration was determined in mitochondria exposed to ONOO- alone or to Ca2+ then ONOO-, and mitochondrial membrane proteins analyzed using proteomics. These studies suggest protein targets revealed by Ca2+ include dehydrogenases and CoA containing enzymes. These data are discussed in the context of the role of mitochondria, Ca2+ and ONOO- in apoptotic signaling.
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