Abstract
Voltage-dependent anion channels (VDACs) are expressed in three isoforms, with common channeling properties and different roles in cell survival. We show that VDAC1 silencing potentiates apoptotic challenges, whereas VDAC2 has the opposite effect. Although all three VDAC isoforms are equivalent in allowing mitochondrial Ca2+ loading upon agonist stimulation, VDAC1 silencing selectively impairs the transfer of the low-amplitude apoptotic Ca2+ signals. Co-immunoprecipitation experiments show that VDAC1, but not VDAC2 and VDAC3, forms complexes with IP3 receptors, an interaction that is further strengthened by apoptotic stimuli. These data highlight a non-redundant molecular route for transferring Ca2+ signals to mitochondria in apoptosis.
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Abbreviations
- [Ca2+]cyt:
-
cytosolic [Ca2+]
- [Ca2+]ER:
-
endoplasmic reticulum [Ca2+]
- [Ca2+]mt:
-
mitochondrial [Ca2+]
- cytAeq:
-
cytosolic aequorin
- ER:
-
endoplasmic reticulum
- erAeqMut:
-
endoplasmic reticulum-targeted mutated aequorin
- GFP:
-
green fluorescent protein
- IP3R:
-
inositol 1,4,5-trisphosphate receptor
- mtAeqMut:
-
mitochondrially targeted mutated aequorin
- mtAeqwt:
-
mitochondrially targeted aequorin
- mtGFP:
-
mitochondrially targeted green fluorescent protein
- OMM:
-
outer mitochondrial membrane
- PGC-1:
-
peroxisome-proliferator activated receptor coactivator-1
- siRNA:
-
small interfering RNA
- TMRM:
-
tetramethylrhodamine methyl esther
- VDAC:
-
voltage-dependent anion channel
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Acknowledgements
This work was supported by grants from the Italian Ministries of Education (PRIN and local funds) and Health, European Union (FP7 ‘MyoAGE’), Italian Space Agency (ASI), NIH (Grant no. 1P01AG025532-01A1), Cariparo Foundation (Padova), the Italian Association for Cancer Research (AIRC), Telethon-Italy and FISM (Multiple Sclerosis) foundations.
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De Stefani, D., Bononi, A., Romagnoli, A. et al. VDAC1 selectively transfers apoptotic Ca2+ signals to mitochondria. Cell Death Differ 19, 267–273 (2012). https://doi.org/10.1038/cdd.2011.92
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DOI: https://doi.org/10.1038/cdd.2011.92
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