title: Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy.
abstract: The mitochondrial phosphate carrier (PiC) is critical for ATP synthesis by serving as the primary means for mitochondrial phosphate import across the inner membrane. In addition to its role in energy production, PiC is hypothesized to have a role in cell death as either a component or a regulator of the mitochondrial permeability transition pore (MPTP) complex. Here, we have generated a mouse model with inducible and cardiac-specific deletion of the Slc25a3 gene (PiC protein). Loss of PiC protein did not prevent MPTP opening, suggesting it is not a direct pore-forming component of this complex. However, Slc25a3 deletion in the heart blunted MPTP opening in response to Ca(2+) challenge and led to a greater Ca(2+) uptake capacity. This desensitization of MPTP opening due to loss or reduction in PiC protein attenuated cardiac ischemic-reperfusion injury, as well as partially protected cells in culture from Ca(2+) overload induced death. Intriguingly, deletion of the Slc25a3 gene from the heart long-term resulted in profound hypertrophy with ventricular dilation and depressed cardiac function, all features that reflect the cardiomyopathy observed in humans with mutations in SLC25A3. Together, these results demonstrate that although the PiC is not a direct component of the MPTP, it can regulate its activity, suggesting a novel therapeutic target for reducing necrotic cell death. In addition, mice lacking Slc25a3 in the heart serve as a novel model of metabolic, mitochondrial-driven cardiomyopathy.
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: J Q
authors.initials: JQ
authors.lastname: Kwong
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Davis
authors.affiliation: Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, MO, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Baines
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Sargent
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Karch
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: T
authors.initials: T
authors.lastname: Huang
authors.affiliation: 1] Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA [2] Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Molkentin
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D009202:Cardiomyopathies / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000235:genetics* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D018384:Oxidative Stress / Q000235:genetics; D028081:Proton-Phosphate Symporters / Q000172:deficiency / Q000235:genetics*
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D028081:Proton-Phosphate Symporters; D002118:Calcium