Activation of the mitochondrial permeability transition pore modulates Ca2+ responses to physiological stimuli in adult neurons

Eur J Neurosci. 2011 Mar;33(5):831-42. doi: 10.1111/j.1460-9568.2010.07576.x. Epub 2011 Jan 24.

Abstract

The participation of mitochondria in cellular and neuronal Ca(2+) homeostatic networks is now well accepted. Yet, critical tests of specific mitochondrial pathways in neuronal Ca(2+) responses have been hampered because the identity of mitochondrial proteins that must be integrated within this dynamic system remain uncertain. One putative pathway for Ca(2+) 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 Ca(2+) 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 Ca(2+) . Our results are the first to demonstrate CyPD-dependent PTP opening in normal neuronal Ca(2+) 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 Ca(2+) overload.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Calcium / metabolism*
  • Cyclophilin D
  • Cyclophilins / genetics
  • Cyclophilins / metabolism
  • Cytosol / metabolism
  • Homeostasis
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Mitochondrial Permeability Transition Pore
  • Neurons / cytology
  • Neurons / metabolism*

Substances

  • Cyclophilin D
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • PPIF protein, mouse
  • Adenosine Triphosphate
  • Cyclophilins
  • Calcium