title: Mitochondrial DNA mutation-elicited oxidative stress, oxidative damage, and altered gene expression in cultured cells of patients with MERRF syndrome.
abstract: Myoclonic epilepsy and ragged-red fibers (MERRF) syndrome is a rare disorder characterized by myoclonus, muscle weakness, cerebellar ataxia, heart conduction block, and dementia. It has been documented that 80-90% of the patients with MERRF syndrome are caused by the A8344G mutation in the tRNA(Lys) gene of mitochondrial DNA (mtDNA). We and other investigators have reported that the mtDNA mutation results in not only inefficient generation of adenosine triphosphate but also increased production of reactive oxygen species (ROS) in cultured cells harboring A8344G mutation of mtDNA. In addition, we found an imbalance in the gene expression of antioxidant enzymes in the skin fibroblasts of MERRF patients. The mRNA, protein, and enzyme activity levels of manganese-superoxide dismutase were increased, but those of Cu,Zn-SOD, catalase, and glutathione peroxidase did not show significant changes. Recently, we showed that the excess ROS could damage voltage-dependent anion channel, prohibitin, Lon protease, and aconitase in the MERRF cells. Moreover, there was a dramatic increase in the gene expression and activity of matrix metalloproteinase 1, which may contribute to the cytoskeleton remodeling involved in the weakness and atrophy of muscle commonly seen in MERRF patients. Taken together, we suggest that mtDNA mutation-elicited oxidative stress, oxidative damage, and altered gene expression are involved in the pathogenesis and progression of MERRF syndrome.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Shi-Bei
authors.initials: SB
authors.lastname: Wu
authors.forename: Yi-Shing
authors.initials: YS
authors.lastname: Ma
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Wu
authors.forename: Yin-Chiu
authors.initials: YC
authors.lastname: Chen
authors.forename: Yau-Huei
authors.initials: YH
authors.lastname: Wei
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D019069:Cell Respiration / Q000502:physiology; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D015870:Gene Expression; D006801:Humans; D017243:MERRF Syndrome / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D020781:Matrix Metalloproteinase 1
references.citation: Mol Genet Metab. 2003 Nov;80(3):321-9
references.pmid: 14680979
references.citation: Neurochem Int. 2000 Aug-Sep;37(2-3):229-41
references.pmid: 10812208
references.citation: J Formos Med Assoc. 2009 Aug;108(8):599-611
references.pmid: 19666347
references.citation: J Neurosci. 2000 Dec 15;20(24):8972-9
references.pmid: 11124972
references.citation: J Cell Biol. 2008 Jan 14;180(1):101-12
references.pmid: 18195103
references.citation: Mitochondrion. 2007 Feb-Apr;7(1-2):106-18
references.pmid: 17307400
references.citation: Electrophoresis. 2006 Apr;27(8):1574-83
references.pmid: 16548050
references.citation: J Neurol Sci. 1991 Sep;105(1):57-60
references.pmid: 1665506
references.citation: J Neurochem. 2009 Nov;111(4):945-55
references.pmid: 19735447
references.citation: Exp Gerontol. 1995 May-Aug;30(3-4):269-90
references.pmid: 7556507
references.citation: Cell. 1990 Jun 15;61(6):931-7
references.pmid: 2112427
references.citation: Proteomics. 2001 Jul;1(7):829-34
references.pmid: 11503207
references.citation: Biochim Biophys Acta. 1997 Aug 22;1361(2):185-97
references.pmid: 9300800
references.citation: Free Radic Res. 2008 Mar;42(3):221-5
references.pmid: 18344116
references.citation: Neurochem Int. 2008 May;52(6):1284-9
references.pmid: 18308427
references.citation: Hum Mol Genet. 2008 Aug 1;17(15):2265-73
references.pmid: 18424449
references.citation: Am J Hypertens. 2008 Oct;21(10):1129-36
references.pmid: 18756259
references.citation: Nat Cell Biol. 2002 Sep;4(9):674-80
references.pmid: 12198491
references.citation: Biochim Biophys Acta. 1995 May 24;1271(1):67-74
references.pmid: 7599228
references.citation: J Bioenerg Biomembr. 2009 Oct;41(5):425-31
references.pmid: 19798558
references.citation: J Biol Chem. 2006 May 19;281(20):14100-10
references.pmid: 16569638
references.citation: Neurobiol Aging. 2006 Jan;27(1):42-53
references.pmid: 16298240
references.citation: Connect Tissue Res. 2008;49(3):197-202
references.pmid: 18661342
references.citation: Curr Neurol Neurosci Rep. 2003 Sep;3(5):423-32
references.pmid: 12914686
references.citation: Biochim Biophys Acta. 2009 Oct;1790(10):1021-9
references.pmid: 19397952
references.citation: Ann N Y Acad Sci. 2005 May;1042:55-63
references.pmid: 15965045
references.citation: Chin J Physiol. 2001 Mar 31;44(1):1-11
references.pmid: 11403514
references.citation: Acta Biochim Pol. 2005;52(2):381-95
references.pmid: 15933766
references.citation: Mol Genet Metab. 2008 May;94(1):78-82
references.pmid: 18180188
references.citation: Science. 1999 Mar 5;283(5407):1482-8
references.pmid: 10066162
references.citation: Nat Cell Biol. 2009 Jul;11(7):852-8
references.pmid: 19543272
references.citation: J Neurol. 2010 May;257(5):774-81
references.pmid: 19960200
references.citation: Mitochondrion. 2007 Feb-Apr;7(1-2):89-95
references.pmid: 17331810
references.citation: Cell Mol Life Sci. 2002 Jan;59(1):143-55
references.pmid: 11852914
references.citation: Biochim Biophys Acta. 2000 Jan 3;1500(1):10-6
references.pmid: 10564713
references.citation: J Cell Sci. 2007 Dec 1;120(Pt 23):4155-66
references.pmid: 18032788
references.citation: Biochem Biophys Res Commun. 1997 Jan 3;230(1):94-9
references.pmid: 9020069
references.citation: FEBS J. 2009 Feb;276(4):1036-47
references.pmid: 19154341
references.citation: J Neurochem. 2002 Sep;82(6):1524-32
references.pmid: 12354300
references.citation: Eur J Hum Genet. 2010 Mar;18(3):324-9
references.pmid: 19809478
references.citation: Arch Biochem Biophys. 1996 Dec 15;336(2):290-6
references.pmid: 8954577
references.citation: Cell. 1988 Nov 18;55(4):601-10
references.pmid: 3180221
references.citation: J Biol Chem. 2002 Feb 22;277(8):5810-5
references.pmid: 11741983
references.citation: J Neurol Sci. 2009 Jun 15;281(1-2):85-92
references.pmid: 19278689
references.citation: J Biol Chem. 1997 Jul 25;272(30):18515-7
references.pmid: 9228011
references.citation: Int J Biochem Cell Biol. 2009 Aug-Sep;41(8-9):1697-707
references.pmid: 19433311
references.citation: Neurochem Res. 2007 Apr-May;32(4-5):757-73
references.pmid: 17191135
references.citation: Neurochem Int. 2008 Sep;53(3-4):95-101
references.pmid: 18598728
references.citation: J Neurotrauma. 2007 May;24(5):772-89
references.pmid: 17518533
references.citation: J Cell Sci. 2009 Nov 1;122(Pt 21):3823-30
references.pmid: 19889967
references.citation: Neuromuscul Disord. 2009 Apr;19(4):275-8
references.pmid: 19269823
references.citation: Biochim Biophys Acta. 2009 Aug;1792(8):783-90
references.pmid: 19477272
references.citation: Biosci Rep. 1997 Feb;17(1):33-42
references.pmid: 9171919
references.citation: Biochem J. 1996 Sep 1;318 ( Pt 2):401-7
references.pmid: 8809026
references.citation: Eur J Biochem. 1999 Jan;259(1-2):462-9
references.pmid: 9914528
references.citation: Muscle Nerve. 2003 Oct;28(4):484-92
references.pmid: 14506721
references.citation: Biochem J. 2003 Aug 15;374(Pt 1):131-6
references.pmid: 12737626
references.citation: Free Radic Res. 2008 May;42(5):415-27
references.pmid: 18551809
references.citation: PLoS One. 2009 Sep 18;4(9):e7095
references.pmid: 19763183
references.citation: Free Radic Biol Med. 2004 Sep 15;37(6):768-84
references.pmid: 15304253
references.citation: Free Radic Biol Med. 2008 Sep 1;45(5):667-78
references.pmid: 18588971
references.citation: J Inherit Metab Dis. 2009 Dec;32 Suppl 1:S339-43
references.pmid: 19924563
references.citation: Adv Clin Chem. 2003;37:83-128
references.pmid: 12619706
references.citation: Brain Res. 1993 Aug 6;618(2):299-302
references.pmid: 8104085
references.citation: Cell Metab. 2006 Mar;3(3):199-210
references.pmid: 16517407
references.citation: Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):5987-91
references.pmid: 15840721
references.citation: Free Radic Biol Med. 2009 Apr 15;46(8):1042-8
references.pmid: 19439239
references.citation: Biochim Biophys Acta. 1999 Feb 9;1410(2):125-45
references.pmid: 10076022
references.citation: Eur J Biochem. 1998 Aug 1;255(3):570-9
references.pmid: 9738895
references.citation: Nature. 2009 Aug 13;460(7257):831-8
references.pmid: 19675643
references.citation: Science. 2006 Oct 20;314(5798):471-4
references.pmid: 17053148
references.citation: Neuromuscul Disord. 1995 Nov;5(6):483-8
references.pmid: 8580730
references.citation: Clin Chem Lab Med. 2006;44(5):589-93
references.pmid: 16681429
references.citation: Mol Cell Biochem. 1997 Sep;174(1-2):215-9
references.pmid: 9309690
references.citation: Proteomics. 2004 Dec;4(12):3943-52
references.pmid: 15526345
references.citation: J Orthop Res. 1991 Jul;9(4):568-75
references.pmid: 1646316
references.citation: Arch Neurol. 2009 Mar;66(3):399-402
references.pmid: 19273760
references.citation: Eur J Biochem. 1978 Jan 16;82(2):563-7
references.pmid: 203456
references.citation: Biochem J. 1999 Sep 15;342 Pt 3:537-44
references.pmid: 10477264
references.citation: J Neurochem. 2008 Jul;106(1):333-46
references.pmid: 18384645
references.citation: Mitochondrion. 2009 Sep;9(5):306-13
references.pmid: 19393775
references.citation: Lancet. 2006 Jul 1;368(9529):70-82
references.pmid: 16815381
references.citation: Free Radic Biol Med. 1997;22(3):515-24
references.pmid: 8981044
references.citation: J Biol Chem. 2007 Jun 15;282(24):17363-74
references.pmid: 17420247
references.citation: Brain. 1994 Jun;117 ( Pt 3):435-43
references.pmid: 8032855
references.citation: Lancet Neurol. 2009 Feb;8(2):205-16
references.pmid: 19161911