Axonal degeneration is mediated by the mitochondrial permeability transition pore.
Axonal degeneration is an active process that has been associated with neurodegenerative conditions triggered by mechanical, metabolic, infectious, toxic, hereditary and inflammatory stimuli. This degenerative process can cause permanent loss of function, so it represents a focus for neuroprotective strategies. Several signaling pathways are implicated in axonal degeneration, but identification of an integrative mechanism for this self-destructive process has remained elusive. Here, we show that rapid axonal degeneration triggered by distinct mechanical and toxic insults is dependent on the activation of the mitochondrial permeability transition pore (mPTP). Both pharmacological and genetic targeting of cyclophilin D, a functional component of the mPTP, protects severed axons and vincristine-treated neurons from axonal degeneration in ex vivo and in vitro mouse and rat model systems. These effects were observed in axons from both the peripheral and central nervous system. Our results suggest that the mPTP is a key effector of axonal degeneration, upon which several independent signaling pathways converge. Since axonal and synapse degeneration are increasingly considered early pathological events in neurodegeneration, our work identifies a potential target for therapeutic intervention in a wide variety of conditions that lead to loss of axons and subsequent functional impairment.
Department of Physiology, Faculty of Biology, Catholic University of Chile, Santiago 8331150, Chile.
Sebastian A
SA
Barrientos
Nicolas W
NW
Martinez
Soonmoon
S
Yoo
Juan S
JS
Jara
Sebastian
S
Zamorano
Claudio
C
Hetz
Jeffery L
JL
Twiss
Jaime
J
Alvarez
Felipe A
FA
Court
D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D002478:Cells, Cultured; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D008297:Male; D051379:Mice; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000081406:Peptidyl-Prolyl Isomerase F; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C000631446:PPIF protein, mouse; D021983:Cyclophilins
Acta Neuropathol. 2004 May;107(5):461-74
15029445
Nat Med. 2008 Oct;14(10):1097-105
18806802
Annu Rev Neurosci. 2010;33:245-67
20345246
Exp Neurol. 1997 Jul;146(1):46-56
9225737
J Neurosci. 2009 Oct 14;29(41):12776-86
19828789
J Biol Chem. 2005 Oct 28;280(43):36334-41
16118205
Prog Neurobiol. 2007 Oct;83(3):174-91
17822833
BMC Neurosci. 2005 Feb 01;6:6
15686598
Nature. 2005 Mar 31;434(7033):652-8
15800626
Eur J Neurosci. 1989;1(1):27-33
12106171
Science. 2005 Feb 25;307(5713):1282-8
15731448
Curr Biol. 2009 Dec 29;19(24):2086-90
19962310
Genes Dev. 2009 Oct 1;23(19):2294-306
19762508
Nat Rev Neurosci. 2005 Nov;6(11):889-98
16224497
Biochem J. 1990 May 15;268(1):153-60
2160810
J Neurocytol. 1986 Aug;15(4):483-96
2427662
J Neurosci Methods. 2004 Mar 15;134(1):23-35
15102500
Biochim Biophys Acta. 2004 Jul 9;1657(2-3):105-14
15238267
Am J Physiol. 1999 Feb;276(2):H496-502
9950850
Nature. 2005 Mar 31;434(7033):658-62
15800627
Proc Natl Acad Sci U S A. 2005 Aug 23;102(34):12005-10
16103352
Dev Biol. 1994 Sep;165(1):63-72
8088451
Brain Res. 2003 Jan 17;960(1-2):99-111
12505662
J Neurosci. 2010 Oct 6;30(40):13291-304
20926655
J Biophys Biochem Cytol. 1958 Sep 25;4(5):551-5
13587548
Neurobiol Dis. 2000 Aug;7(4):416-28
10964612
J Cell Biol. 2005 Aug 1;170(3):349-55
16043516
J Cell Biol. 1962 Feb;12:361-83
14005486
J Clin Invest. 2004 Jan;113(2):231-42
14722615
J Mol Cell Cardiol. 2009 Jun;46(6):821-31
19265700
J Neurosci. 2009 Mar 25;29(12):3908-19
19321787
Toxicol Appl Pharmacol. 1997 Apr;143(2):233-44
9144441
J Biol Chem. 1997 Feb 7;272(6):3346-54
9013575
J Neurosci. 2009 May 13;29(19):6276-84
19439605
Neuron. 2003 Jul 17;39(2):217-25
12873380
Brain. 2005 Feb;128(Pt 2):405-16
15644421
Nat Neurosci. 2001 Dec;4(12):1199-206
11770485
Trends Neurosci. 2002 Oct;25(10):532-7
12220882
J Neurosci. 2005 Jan 26;25(4):778-91
15673657
Cell Death Differ. 2003 Feb;10(2):260-1
12700655
Anal Biochem. 2001 Aug 15;295(2):220-6
11488625
J Neurosci. 1995 Oct;15(10):6445-52
7472407
Nat Med. 2005 May;11(5):572-7
15821747
Science. 2004 Aug 13;305(5686):1010-3
15310905
Curr Biol. 2003 Apr 15;13(8):669-73
12699624
J Biol Chem. 1976 Aug 25;251(16):5069-77
134035
FASEB J. 2006 Dec;20(14):2573-5
17068110
J Neurotrauma. 2000 May;17(5):431-40
10833062
J Neurosci. 1999 Jun 15;19(12):4718-26
10366605
PLoS Biol. 2010 Jan 26;8(1):e1000300
20126265
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 Neurosci. 2009 May 20;29(20):6526-34
19458223
FEBS Lett. 2004 Jun 1;567(1):96-102
15165900
Curr Biol. 2004 Feb 17;14(4):326-30
14972684
J Bioenerg Biomembr. 1999 Aug;31(4):335-45
10665524
Cell. 1991 Aug 23;66(4):807-15
1715244
Nat Neurosci. 2009 Apr;12(4):387-9
19287387
J Biol Chem. 1949 Feb;177(2):751-66
18110453
J Neurosci. 1998 Jul 15;18(14):5151-9
9651198
Neuron. 2008 Jul 31;59(2):214-25
18667150
Eur J Neurosci. 1990;2(9):802-8
12106282
Neuroscience. 2003;122(3):617-26
14622905
J Neurol Sci. 2005 Jun 15;233(1-2):3-13
15899499
Exp Neurol. 2009 Aug;218(2):333-46
19272377
Nat Protoc. 2008;3(7):1228-39
18600228
Am J Anat. 1972 Jan;133(1):51-83
4109486
J Neurosci. 1995 Nov;15(11):7727-33
7472523