S-nitrosylation of Drp1 links excessive mitochondrial fission to neuronal injury in neurodegeneration.
Neurons are known to use large amounts of energy for their normal function and activity. In order to meet this demand, mitochondrial fission, fusion, and movement events (mitochondrial dynamics) control mitochondrial morphology, facilitating biogenesis and proper distribution of mitochondria within neurons. In contrast, dysfunction in mitochondrial dynamics results in reduced cell bioenergetics and thus contributes to neuronal injury and death in many neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease, and Huntington's disease. We recently reported that amyloid-beta peptide, thought to be a key mediator of AD pathogenesis, engenders S-nitrosylation and thus hyperactivation of the mitochondrial fission protein Drp1. This activation leads to excessive mitochondrial fragmentation, bioenergetic compromise, and synaptic damage in models of AD. Here, we provide an extended commentary on our findings of nitric oxide-mediated abnormal mitochondrial dynamics.
Nakamura
Tomohiro
T
Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Cieplak
Piotr
P
Cho
Dong-Hyung
DH
Godzik
Adam
A
Lipton
Stuart A
SA
D000544:Alzheimer Disease / Q000473:pathology; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000473:pathology*; D009474:Neurons / Q000473:pathology*; D009569:Nitric Oxide / Q000378:metabolism*
D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D009569:Nitric Oxide; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins
J Neurosci. 2004 Jul 7;24(27):6049-56
15240796
Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14503-8
18799731
Exp Neurol. 2009 Sep;219(1):266-73
19500570
J Neurochem. 2009 May;109 Suppl 1:153-9
19393022
Neuron. 2002 Jul 3;35(1):9-12
12123602
Nature. 2006 Oct 19;443(7113):787-95
17051205
Neurobiol Dis. 2006 May;22(2):388-400
16473015
Nature. 1993 Aug 5;364(6437):535-7
7687749
Proc Natl Acad Sci U S A. 2006 Jul 11;103(28):10793-8
16818890
N Engl J Med. 1994 Mar 3;330(9):613-22
7905600
EMBO J. 2006 Aug 9;25(15):3618-26
16874301
Neurobiol Dis. 2005 Apr;18(3):459-65
15755672
J Biol Chem. 2004 Nov 26;279(48):50286-94
15364948
Nature. 1988 Nov 24;336(6197):385-8
2904125
J Cell Biol. 2005 Sep 26;170(7):1021-7
16186251
Nat Rev Drug Discov. 2004 Mar;3(3):205-14
15031734
Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2169-74
18250306
J Biol Chem. 2009 Aug 21;284(34):22938-51
19546216
Brain Res Rev. 2009 Jun;61(1):33-48
19394359
Chem Biol. 2008 Dec 22;15(12):1307-16
19101475
Antioxid Redox Signal. 2007 Oct;9(10):1647-58
17696767
Mol Cell. 2008 Aug 22;31(4):586-597
18722182
Proc Natl Acad Sci U S A. 1990 Feb;87(4):1620-4
2154753
Cell Death Differ. 2003 Jul;10(7):757-60
12815458
Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1295-300
16432212
Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1638-43
18230723
J Neurosci. 2007 May 16;27(20):5394-404
17507561
Hum Mol Genet. 2005 Oct 1;14(19):2871-80
16115812
J Biol Chem. 2004 Aug 20;279(34):35967-74
15208300
J Neurosci. 2001 May 1;21(9):3017-23
11312286
Nat Rev Neurosci. 2001 May;2(5):325-34
11331916
Nat Rev Neurosci. 2006 Mar;7(3):207-19
16495942
Free Radic Biol Med. 2008 Jun 1;44(11):1960-9
18395527
Nature. 1993 Aug 12;364(6438):626-32
8394509
Nat Rev Mol Cell Biol. 2007 Feb;8(2):101-12
17245412
Nat Rev Neurosci. 2008 Jul;9(7):505-18
18568013
J Alzheimers Dis. 2010;20 Suppl 2:S513-26
20463395
J Neurosci. 2009 Jul 15;29(28):9090-103
19605646
Biomed Pharmacother. 2004 Jan;58(1):39-46
14739060
Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7631-6
9636201
Cell. 2009 Dec 24;139(7):1342-52
20064379
EMBO Rep. 2007 Oct;8(10):939-44
17721437
Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):7105-9
7624378
Curr Opin Cell Biol. 2006 Aug;18(4):453-9
16781135
Mol Cell Proteomics. 2007 May;6(5):845-59
16854843
Nat Neurosci. 2002 Aug;5(8):731-6
12089530
Cell Death Differ. 2007 Mar;14(3):462-71
17053808
J Neurosci. 2007 Nov 7;27(45):12413-8
17989306
Cell Death Differ. 2009 Jun;16(6):899-909
19300456
Nat Genet. 2000 Oct;26(2):207-10
11017079
Hum Mol Genet. 2009 Feb 15;18(4):737-52
19039036
J Biol Chem. 2007 Jul 27;282(30):21583-7
17553808
J Cell Biol. 2007 Jul 2;178(1):71-84
17606867
Nature. 2006 Dec 7;444(7120):766-9
17122778
Science. 2009 Apr 3;324(5923):102-5
19342591
J Cell Sci. 2007 Feb 1;120(Pt 3):492-501
17251380
Nat Rev Drug Discov. 2006 Oct;5(10):845-54
17016425
Nitric Oxide. 2005 Mar;12(2):121-6
15740986
Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19318-23
19050078
Nature. 2000 Feb 3;403(6769):567-71
10676968
Cell. 2004 Dec 17;119(6):873-87
15607982
Trends Pharmacol Sci. 1998 Aug;19(8):328-34
9745361
Nat Rev Mol Cell Biol. 2004 Feb;5(2):133-47
15040446
J Cell Biol. 2007 May 7;177(3):439-50
17470634
Neurology. 1994 Jun;44(6):1090-6
8208407
Ann Neurol. 1999 Jan;45(1):25-32
9894873
Nat Cell Biol. 2001 Oct;3(10):922-6
11584275
Nature. 1991 Jun 27;351(6329):714-8
1712077
J Biol Chem. 2007 Apr 13;282(15):11521-9
17301055
Nat Rev Mol Cell Biol. 2005 Aug;6(8):657-63
16025099
Mol Cell Biochem. 1994 Nov 9;140(1):1-22
7877593
J Alzheimers Dis. 2006 Jul;9(2):119-26
16873959
J Biol Chem. 2009 May 15;284(20):13843-13855
19279012
Proc Natl Acad Sci U S A. 2006 Jan 24;103(4):1012-7
16418269
J Neurochem. 2008 Jan;104(2):420-34
17953654
Curr Opin Cell Biol. 2003 Dec;15(6):706-16
14644195
FEBS Lett. 1994 May 23;345(1):50-4
8194600
Neuron. 2009 Jun 25;62(6):788-801
19555648
EMBO J. 2006 Aug 23;25(16):3900-11
16874299
Nat Genet. 2004 May;36(5):449-51
15064763
EMBO Rep. 2006 Oct;7(10):1019-22
16936636
Hum Genet. 2005 Jan;116(1-2):23-7
15549395
J Biol Chem. 2009 Jul 10;284(28):18754-66
19389700
N Engl J Med. 2007 Apr 26;356(17):1736-41
17460227
Traffic. 2007 Dec;8(12):1668-1675
17944806
Proc Natl Acad Sci U S A. 2008 Mar 18;105(11):4441-6
18332434
Neuroscience. 2008 Oct 28;156(4):898-910
18790019
EMBO J. 2007 Jan 24;26(2):559-66
17170701
Nat Rev Drug Discov. 2006 Feb;5(2):160-70
16424917