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 Ca2+ challenge and led to a greater Ca2+ 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 Ca2+ 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.
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Abbreviations
- α-MHC:
-
α-myosin heavy chain
- AdCre:
-
adenovirus-expressing Cre recombinase
- Adβgal:
-
adenovirus-expressing β-galactosidase
- ANT:
-
adenine nucleotide translocator
- ATR:
-
atractyloside
- CypD:
-
cyclophilin D
- CsA:
-
cyclosporine A
- fl:
-
loxP site
- MCM:
-
αMHC-MerCreMer transgene
- MEFs:
-
mouse embryonic fibroblasts
- MPTP:
-
mitochondrial permeability transition pore
- Pi:
-
inorganic phosphate
- PiC:
-
mitochondrial phosphate carrier
- OXPHOS:
-
mitochondrial oxidative phosphorylation
- ROS:
-
reactive oxygen species
- SR:
-
sarcoplasmic reticulum
- WT:
-
wild type
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Acknowledgements
This work was supported by grants from the National Institutes of Health and the Howard Hughes Medical Institute (to JDM). JQK was supported by an American Heart Association postdoctoral fellowship from the Great Rivers Affiliate.
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Kwong, J., Davis, J., Baines, C. et al. Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy. Cell Death Differ 21, 1209–1217 (2014). https://doi.org/10.1038/cdd.2014.36
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DOI: https://doi.org/10.1038/cdd.2014.36
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