Activation of the mitochondrial permeability transition pore modulates Ca2+ responses to physiological stimuli in adult neurons.
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.
Vollum Institute and Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Anna
A
Barsukova
Alexander
A
Komarov
György
G
Hajnóczky
Paolo
P
Bernardi
Dennis
D
Bourdette
Michael
M
Forte
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000235:genetics / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D006706:Homeostasis; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D009474:Neurons / Q000166:cytology / Q000378:metabolism*
D000081406:Peptidyl-Prolyl Isomerase F; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C000631446:PPIF protein, mouse; D000255:Adenosine Triphosphate; D021983:Cyclophilins; D002118:Calcium
Exp Neurol. 2009 Aug;218(2):171-82
19236863
Nature. 2005 Mar 31;434(7033):658-62
15800627
Apoptosis. 2007 May;12(5):815-33
17294078
Proc Natl Acad Sci U S A. 2005 Aug 23;102(34):12005-10
16103352
J Neurobiol. 1992 Nov;23(9):1261-76
1361523
Physiol Rev. 1999 Oct;79(4):1127-55
10508231
Ann N Y Acad Sci. 2008 Dec;1147:395-412
19076459
IUBMB Life. 2001 Sep-Nov;52(3-5):197-204
11798033
Biochim Biophys Acta. 2008 Jul-Aug;1777(7-8):953-64
18471431
Cell Calcium. 2006 Nov-Dec;40(5-6):553-60
17074387
Biochim Biophys Acta. 2009 Nov;1787(11):1291-308
19161975
Biochim Biophys Acta. 2009 Nov;1787(11):1416-24
19298790
Endocrinology. 2004 Jul;145(7):3065-73
15033916
J Biol Chem. 2001 Jun 29;276(26):23329-40
11323421
J Mol Cell Cardiol. 2009 Jun;46(6):775-80
19303419
Nature. 2004 Jan 22;427(6972):360-4
14737170
FEBS Lett. 1994 Jul 11;348(2):211-5
8034044
J Biol Chem. 1998 Jan 23;273(4):2146-52
9442055
Nature. 2005 Mar 31;434(7033):652-8
15800626
J Biol Chem. 2003 Oct 24;278(43):42273-82
12907683
Physiol Rev. 2000 Jan;80(1):315-60
10617771
Curr Neurol Neurosci Rep. 2009 Sep;9(5):411-7
19664372
J Bioenerg Biomembr. 1996 Apr;28(2):131-8
9132411
J Neurosci. 2007 Jul 11;27(28):7469-75
17626207
Nat Med. 2008 Oct;14(10):1097-105
18806802
J Biol Chem. 2003 Oct 3;278(40):39224-34
12874292
Brain Res Dev Brain Res. 1998 Nov 1;111(1):43-50
9804886
Trends Pharmacol Sci. 2006 Aug;27(8):402-9
16822554
Nature. 1998 Jul 9;394(6689):192-5
9671304
Aging Cell. 2007 Jun;6(3):337-50
17328689
EMBO J. 2001 Apr 17;20(8):1863-74
11296220
J Biol Chem. 2001 Apr 13;276(15):12030-4
11134038
Curr Mol Med. 2008 Mar;8(2):119-30
18336292
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3197-202
11248055
Biochim Biophys Acta. 2009 Nov;1787(11):1342-51
19341702
J Biol Chem. 2006 Apr 28;281(17):11658-68
16517608
Biochim Biophys Acta. 2009 May;1787(5):335-44
19268425
FASEB J. 2002 Apr;16(6):607-9
11919169
Nat Genet. 2003 Jun;34(2):135-41
12776115
J Comp Neurol. 2006 Sep 10;498(2):277-94
16856139
FEBS J. 2005 Aug;272(16):4013-22
16098185
Physiology (Bethesda). 2008 Apr;23:84-94
18400691
Cell Calcium. 2000 Nov-Dec;28(5-6):307-16
11115370
Eur J Biochem. 1999 Sep;264(3):687-701
10491114
Am J Physiol Cell Physiol. 2004 Oct;287(4):C817-33
15355853
Curr Opin Neurobiol. 2006 Jun;16(3):281-7
16698262
J Bioenerg Biomembr. 2004 Aug;36(4):277-81
15377857
J Neurosci. 2009 Feb 25;29(8):2588-96
19244535
Biophys J. 1999 Feb;76(2):725-34
9929477
J Biol Chem. 2009 May 29;284(22):15117-25
19346250
Am J Physiol Cell Physiol. 2007 Feb;292(2):C641-57
17092996
FEBS J. 2006 May;273(10):2077-99
16649987
Proc Natl Acad Sci U S A. 2007 May 1;104(18):7558-63
17463082
J Biol Chem. 2005 May 13;280(19):18558-61
15792954
Cell Calcium. 2005 Feb;37(2):129-36
15589993
Cell Death Differ. 2007 Jul;14(7):1267-74
17431419
Lancet Neurol. 2009 Mar;8(3):280-91
19233038
Nat Rev Mol Cell Biol. 2003 Jul;4(7):579-86
12838340
Biochim Biophys Acta. 2009 Nov;1787(11):1352-62
19527680