Present address: Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR 97239, USA.
Activation of the mitochondrial permeability transition pore modulates Ca2+ responses to physiological stimuli in adult neurons
Article first published online: 24 JAN 2011
© 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd
European Journal of Neuroscience
Volume 33, Issue 5, pages 831–842, March 2011
How to Cite
Barsukova, A., Komarov, A., Hajnóczky, G., Bernardi, P., Bourdette, D. and Forte, M. (2011), Activation of the mitochondrial permeability transition pore modulates Ca2+ responses to physiological stimuli in adult neurons. European Journal of Neuroscience, 33: 831–842. doi: 10.1111/j.1460-9568.2010.07576.x
- Issue published online: 8 MAR 2011
- Article first published online: 24 JAN 2011
- Received 31 August 2010, revised 18 October 2010, accepted 1 December 2010
- calcium homeostasis;
- cortical neurons;
- mutant mice;
- neurodegeneration neuroprotection
The participation of mitochondria in cellular and neuronal Ca2+ homeostatic networks is now well accepted. Yet, critical tests of specific mitochondrial pathways in neuronal Ca2+ responses have been hampered because the identity of mitochondrial proteins that must be integrated within this dynamic system remain uncertain. One putative pathway for Ca2+ efflux from mitochondria exists through the formation of the permeability transition pore (PTP) that is often associated with cellular and neuronal death. Here, we have evaluated neuronal Ca2+ dynamics and the PTP in single adult neurons in wild-type mice and those missing cyclophilin D (CyPD), a key regulator of the PTP. Using high-resolution time-lapse imaging, we demonstrate that PTP opening only follows simultaneous activation with two physiological stimuli that generate critical threshold levels of cytosolic and mitochondrial Ca2+. Our results are the first to demonstrate CyPD-dependent PTP opening in normal neuronal Ca2+ homeostatic mechanisms not leading to activation of cell death pathways. As neurons in mice lacking CyPD are protected in a number of neurodegenerative disease models, the results suggest that improved viability of CyPD-knockout animals in these pathological states may be due to the transient, rather than persistent, activation of the PTP in mutant mitochondria, thereby shielding neurons from cytoplasmic Ca2+ overload.