Abstract
p66Shc, a redox enzyme that enhances reactive oxygen species (ROS) production by mitochondria, promotes T cell apoptosis. We have addressed the mechanisms regulating p66Shc-dependent apoptosis in T cells exposed to supraphysiological increases in [Ca2+]c. p66Shc expression resulted in profound mitochondrial dysfunction in response to the Ca2+ ionophore A23187, as revealed by dissipation of mitochondrial transmembrane potential, cytochrome c release and decreased ATP levels. p66Shc expression also caused a dramatic alteration in the cells’ Ca2+-handling ability, which resulted in Ca2+ overload after A23187 treatment. The impairment in Ca2+ homeostasis was ROS dependent and caused by defective Ca2+ extrusion due at least in part to decreased plasma membrane ATPase (PMCA) expression. Both effects of p66Shc required Ca2+-dependent serine-36 phosphorylation. The mitochondrial effects of p66Shc were potentiated by but not strictly dependent on the rise in [Ca2+]c. Thus, Ca2+-dependent p66Shc phosphorylation causes both mitochondrial dysfunction and impaired Ca2+ homeostasis, which synergize in promoting T cell apoptosis.
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Abbreviations
- PTP:
-
permeability transition pore
- ROS:
-
reactive oxygen species
- cPLA2:
-
cytosolic phospholipase A2
- PMCA:
-
plasma membrane ATPase
- GFP:
-
green fluorescent protein
- NF-AT:
-
nuclear factor of activated T cells
- TMRM:
-
tetramethylrhodamine methyl ester
- AICD:
-
activation-induced cell death
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Acknowledgements
We thank Sonia Grassini, Eugenio Paccagnini and Luigi Federico Falso for technical assistance; Romano Dallai for useful advice and John L. Telford for critical reading of the manuscript. This work was supported by grants from AIRC (to CTB) and the MIUR (to CTB and PB). The authors have no financial conflicts of interest.
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Pellegrini, M., Finetti, F., Petronilli, V. et al. p66SHC promotes T cell apoptosis by inducing mitochondrial dysfunction and impaired Ca2+ homeostasis. Cell Death Differ 14, 338–347 (2007). https://doi.org/10.1038/sj.cdd.4401997
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DOI: https://doi.org/10.1038/sj.cdd.4401997
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