title: Mitochondrial dysfunction and neurodegeneration in multiple sclerosis.
abstract: Multiple sclerosis (MS) has traditionally been considered an autoimmune inflammatory disorder leading to demyelination and clinical debilitation as evidenced by our current standard anti-inflammatory and immunosuppressive treatment regimens. While these approaches do control the frequency of clinical relapses, they do not prevent the progressive functional decline that plagues many people with MS. Many avenues of research indicate that a neurodegenerative process may also play a significant role in MS from the early stages of disease, and one of the current hypotheses identifies mitochondrial dysfunction as a key contributing mechanism. We have hypothesized that pathological permeability transition pore (PTP) opening mediated by reactive oxygen species (ROS) and calcium dysregulation is central to mitochondrial dysfunction and neurodegeneration in MS. This focused review highlights recent evidence supporting this hypothesis, with particular emphasis on our in vitro and in vivo work with the mitochondria-targeted redox enzyme p66ShcA.
authors.affiliation: Vollum Institute, Oregon Health and Science University Portland, OR, USA ; Department of Neurology, Oregon Health and Science University Portland, OR, USA.
authors.forename: Kimmy
authors.initials: K
authors.lastname: Su
authors.forename: Dennis
authors.initials: D
authors.lastname: Bourdette
authors.forename: Michael
authors.initials: M
authors.lastname: Forte
keywords: mitochondria; multiple sclerosis; neurodegeneration; neuronal viability; p66ShcA
references.citation: Proc Natl Acad Sci U S A. 2013 Apr 9;110(15):5887-92
references.pmid: 23530243
references.citation: Brain. 2000 Feb;123 ( Pt 2):308-17
references.pmid: 10648438
references.citation: Eur J Neurosci. 2012 Feb;35(4):562-71
references.pmid: 22277070
references.citation: Science. 2007 Feb 2;315(5812):659-63
references.pmid: 17272725
references.citation: Neurology. 2008 Apr 15;70(16):1353-7
references.pmid: 18413589
references.citation: Proc Natl Acad Sci U S A. 2005 Aug 23;102(34):12005-10
references.pmid: 16103352
references.citation: J Neurol. 2005 Sep;252 Suppl 3:iii3-iii9
references.pmid: 16170498
references.citation: Biochimie. 2007 Sep;89(9):1107-12
references.pmid: 17400358
references.citation: Aging Cell. 2011 Feb;10(1):55-65
references.pmid: 21040401
references.citation: Cell. 2005 Jul 29;122(2):221-33
references.pmid: 16051147
references.citation: Trends Cell Biol. 2007 Sep;17(9):422-7
references.pmid: 17804237
references.citation: Dev Cell. 2002 Jan;2(1):55-67
references.pmid: 11782314
references.citation: Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):4820-5
references.pmid: 10220377
references.citation: Eur J Biochem. 1999 Aug;263(3):709-16
references.pmid: 10469134
references.citation: Aging (Albany NY). 2009 Jan 30;1(2):254-65
references.pmid: 20157513
references.citation: Front Physiol. 2012 Jul 20;3:285
references.pmid: 22833725
references.citation: Ann N Y Acad Sci. 2003 Jun;991:111-9
references.pmid: 12846980
references.citation: Mult Scler. 2005 Dec;11(6):646-51
references.pmid: 16320723
references.citation: N Engl J Med. 1998 Jan 29;338(5):278-85
references.pmid: 9445407
references.citation: Brain. 2003 Nov;126(Pt 11):2528-36
references.pmid: 12902314
references.citation: Aging Cell. 2012 Feb;11(1):162-8
references.pmid: 22081964
references.citation: Neurobiol Dis. 2008 May;30(2):162-73
references.pmid: 18342527
references.citation: Nature. 2005 Mar 31;434(7033):658-62
references.pmid: 15800627
references.citation: Front Physiol. 2013 May 10;4:95
references.pmid: 23675351
references.citation: EMBO J. 1997 Feb 17;16(4):706-16
references.pmid: 9049300
references.citation: J Mol Cell Cardiol. 1993 Dec;25(12):1461-9
references.pmid: 7512654
references.citation: J Neurotrauma. 2001 Oct;18(10):977-91
references.pmid: 11686498
references.citation: Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):2112-6
references.pmid: 12571362
references.citation: Brain Res Mol Brain Res. 2004 Mar 17;122(1):71-8
references.pmid: 14992817
references.citation: Ann Neurol. 2000 Dec;48(6):893-901
references.pmid: 11117546
references.citation: J Neurol Sci. 2000 Aug 15;177(2):95-103
references.pmid: 10980305
references.citation: Nature. 1999 Nov 18;402(6759):309-13
references.pmid: 10580504
references.citation: Science. 2007 Feb 2;315(5812):607-9
references.pmid: 17272709
references.citation: Brain. 2005 Nov;128(Pt 11):2705-12
references.pmid: 16230320
references.citation: Biochim Biophys Acta. 1994 Aug 30;1187(2):255-9
references.pmid: 7521212
references.citation: Ann Neurol. 2008 Sep;64(3):255-65
references.pmid: 18661561
references.citation: FEBS J. 2006 May;273(10):2077-99
references.pmid: 16649987
references.citation: Neurology. 2001 Oct 9;57(7):1248-52
references.pmid: 11591844
references.citation: Proc Natl Acad Sci U S A. 2007 May 1;104(18):7558-63
references.pmid: 17463082
references.citation: Mol Biol Cell. 2002 Dec;13(12):4343-54
references.pmid: 12475957
references.citation: J Biol Chem. 2005 May 13;280(19):18558-61
references.pmid: 15792954
references.citation: Brain. 2002 Oct;125(Pt 10):2202-12
references.pmid: 12244078
references.citation: J Physiol. 2003 Oct 15;552(Pt 2):335-44
references.pmid: 14561818
references.citation: Biosci Rep. 1997 Feb;17(1):43-52
references.pmid: 9171920
references.citation: N Engl J Med. 2000 Sep 28;343(13):938-52
references.pmid: 11006371
references.citation: Ann Neurol. 2006 Mar;59(3):478-89
references.pmid: 16392116
references.citation: Free Radic Res. 2007 Oct;41(10):1099-108
references.pmid: 17886031
references.citation: Brain. 1998 Jan;121 ( Pt 1):103-13
references.pmid: 9549491
references.citation: Antioxid Redox Signal. 2010 Aug 1;13(3):279-347
references.pmid: 20001744
references.citation: Nat Med. 2011 Apr;17(4):495-9
references.pmid: 21441916
references.citation: J Neurosci. 1998 Jul 15;18(14):5151-9
references.pmid: 9651198
references.citation: Diabetes. 2006 Jun;55(6):1642-50
references.pmid: 16731826
references.citation: J Neurol Sci. 2003 Feb 15;206(2):165-71
references.pmid: 12559505
references.citation: Stroke. 2002 Mar;33(3):816-24
references.pmid: 11872909
references.citation: Antioxid Redox Signal. 2009 Sep;11(9):2095-104
references.pmid: 19203217
references.citation: Ann N Y Acad Sci. 2008 Dec;1147:112-21
references.pmid: 19076436
references.citation: Neurobiol Dis. 2006 Apr;22(1):40-9
references.pmid: 16289867
references.citation: FASEB J. 2005 Jul;19(9):1088-95
references.pmid: 15985532
references.citation: Lab Invest. 2008 Jul;88(7):750-60
references.pmid: 18490896