Abstract 19236: Mapping the Role of the Mitochondrial Phosphate Carrier in Cardiomyocyte Life and Death
Under pathologic conditions, mitochondria from cardiomyocytes experience a change in the highly selective transport of ions and metabolites to a non-selective permeability state. The Mitochondrial Permeability Transition Pore (MPTP) is a voltage-sensitive unselective channel thought to initiate such changes resulting in necrotic cell death during heart disease. While the biochemical behavior of the MPTP has been characterized in extenso, its molecular identity has remained an open question. Previous evidence suggesting Voltage Dependent Anion Channels and Adenine Nucleotide Translocators as putative components of this pore has been casted in doubt as genetic models lacking such proteins still exhibit an MPTP. So far, the mitochondrial Cyclophilin D (CypD) is the only widely accepted MPTP regulator. CypD is known to bind to proteins in the mitochondria such as the F0F1-ATP synthase lateral stalk and the Mitochondrial Phosphate Carrier (PiC) among others. Here we demonstrate that an N-terminal segment of CypD binds the C-terminus of the PiC by using pulldown assays and molecular docking simulations. In addition, we have generated three different transgenic mouse lines overexpressing the PiC at a medium and high level and a double transgenic line co-expressing PiC and CypD. Our results show that cardiac-specific PiC overexpression at the high level results in an MPTP with lesser sensitivity to Ca2+, possibly due the ability of Pi to buffer matrix Ca2+. These results suggest CypD binds to the PiC thus contributing to MPTP regulation.
- © 2012 by American Heart Association, Inc.