Abstract
Ca2+-mediated mitochondrial permeability transition (mPT) is the final common pathway of stress-induced cell death in many major pathologies, but its regulation in intact cells is poorly understood. Here we report that the mitochondrial carrier SCaMC-1/SLC25A24 mediates ATP-Mg2−/Pi2− and/or HADP2−/Pi2− uptake into the mitochondria after an increase in cytosolic [Ca2+]. ATP and ADP contribute to Ca2+ buffering in the mitochondrial matrix, resulting in desensitization of the mPT. Comprehensive gene expression analysis showed that SCaMC-1 overexpression is a general feature of transformed and cancer cells. Knockdown of the transporter led to vast reduction of mitochondrial Ca2+ buffering capacity and sensitized cells to mPT-mediated necrotic death triggered by oxidative stress and Ca2+ overload. These findings revealed that SCaMC-1 exerts a negative feedback control between cellular Ca2+ overload and mPT-dependent cell death, suggesting that the carrier might represent a novel target for cancer therapy.
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Abbreviations
- [Ca2+]cyt:
-
cytosolic [Ca2+]
- [Ca2+]m:
-
mitochondrial [Ca2+]
- ANT:
-
adenine nucleotide translocator
- BKA:
-
bongkrekic acid
- CAT:
-
carboxyatractyloside
- CRC:
-
Ca2+ retention capacity
- CsA:
-
cyclosporin-A
- CyP-D:
-
cyclophilin-D
- cytAEQ:
-
cytosolic aequorin
- ER:
-
endoplasmic reticulum
- IC:
-
intracellular
- IMM:
-
inner mitochondrial membrane
- IP3:
-
inositol-1,4,5-trisphosphate
- MCU:
-
mitochondrial Ca2+ uniporter
- mPT:
-
mitochondrial permeability transition
- mPTP:
-
mitochondrial permeability transition pore
- mtAEQmut:
-
low-affinity mitochondrial aequorin
- mtAEQwt:
-
mitochondrial aequorin
- RR:
-
ruthenium red
- ROS:
-
reactive oxygen species
- VDAC:
-
voltage-dependent anion channel
- ΔΨ:
-
mitochondrial membrane potential
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Acknowledgements
We thank Dr. María Sánchez-Aragó, Dr. Laura Formentini, Laura Sánchez-Cenizo and María Royo for help, reagents and comments; Dr. Claudia Castillo for help with data analysis; and Alejandro Arandilla for technical assistance. We also thank Dr. Paolo Bernardi and Dr. Andrea Rasola for the supply of plasmid pcDNA3-FLAG-CyP-D. This work was supported by grants from Ministerio de Educación y Ciencia (BFU2008-04084/BMC), Comunidad de Madrid (S-GEN-0269-2006 MITOLAB-CM), the European Union (LSHM-CT-2006-518153), and CIBERER (an initiative of the ISCIII) to JS; by grants from the ISCIII (PI080610) to AdelA; and by an institutional grant from the Fundación Ramón Areces to the Centro de Biología Molecular Severo Ochoa. GS was supported by Parkinson's UK (G-0905). JT is a recipient of a fellowship from Comunidad de Madrid.
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Traba, J., del Arco, A., Duchen, M. et al. SCaMC-1 promotes cancer cell survival by desensitizing mitochondrial permeability transition via ATP/ADP-mediated matrix Ca2+ buffering. Cell Death Differ 19, 650–660 (2012). https://doi.org/10.1038/cdd.2011.139
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DOI: https://doi.org/10.1038/cdd.2011.139
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