Abnormal mitochondrial dynamics, mitochondrial loss and mutant huntingtin oligomers in Huntington's disease: implications for selective neuronal damage.
The purpose of our study was to determine the relationship between mutant huntingtin (Htt) and mitochondrial dynamics in the progression of Huntington's disease (HD). We measured the mRNA levels of electron transport chain genes, and mitochondrial structural genes, Drp1 (dynamin-related protein 1), Fis1 (fission 1), Mfn1 (mitofusin 1), Mfn2 (mitofusin 2), Opa1 (optric atrophy 1), Tomm40 (translocase of outermembrane 40) and CypD (cyclophilin D) in grade III and grade IV HD patients and controls. The mutant Htt oligomers and the mitochondrial structural proteins were quantified in the striatum and frontal cortex of HD patients. Changes in expressions of the electron transport chain genes were found in HD patients and may represent a compensatory response to mitochondrial damage caused by mutant Htt. Increased expression of Drp1 and Fis1 and decreased expression of Mfn1, Mfn2, Opa1 and Tomm40 were found in HD patients relative to the controls. CypD was upregulated in HD patients, and this upregulation increased as HD progressed. Significantly increased immunoreactivity of 8-hydroxy-guanosine was found in the cortical specimens from stage III and IV HD patients relative to controls, suggesting increased oxidative DNA damage in HD patients. In contrast, significantly decreased immunoreactivities of cytochrome oxidase 1 and cytochrome b were found in HD patients relative to controls, indicating a loss of mitochondrial function in HD patients. Immunoblotting analysis revealed 15, 25 and 50 kDa mutant Htt oligomers in the brain specimens of HD patients. All oligomeric forms of mutant Htt were significantly increased in the cortical tissues of HD patients, and mutant Htt oligomers were found in the nucleus and in mitochondria. The increase in Drp1, Fis1 and CypD and the decrease in Mfn1 and Mfn2 may be responsible for abnormal mitochondrial dynamics that we found in the cortex of HD patients, and may contribute to neuronal damage in HD patients. The presence of mutant Htt oligomers in the nucleus of HD neurons and in mitochondria may disrupt neuronal functions. Based on these findings, we propose that mutant Htt in association with mitochondria imbalance and mitochondrial dynamics impairs axonal transport of mitochondria, decreases mitochondrial function and damages neurons in affected brain regions of HD patients.
Neurogenetics Laboratory, Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA.
Ulziibat
U
Shirendeb
Arubala P
AP
Reddy
Maria
M
Manczak
Marcus J
MJ
Calkins
Peizhong
P
Mao
Danilo A
DA
Tagle
P Hemachandra
PH
Reddy
D001369:Axons / Q000378:metabolism* / Q000473:pathology; D001692:Biological Transport / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage / Q000235:genetics; D045222:Electron Transport Chain Complex Proteins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
D045222:Electron Transport Chain Complex Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger
Hum Mol Genet. 2007 Apr 1;16(7):783-97
17356014
Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14503-8
18799731
J Biol Chem. 2005 Oct 28;280(43):36464-73
16085648
Trends Neurosci. 1999 Jun;22(6):248-55
10354600
Nat Neurosci. 2002 Aug;5(8):731-6
12089530
J Psychiatry Neurosci. 2006 Jan;31(1):21-9
16496032
Ann Neurol. 1997 May;41(5):646-53
9153527
Ann Neurol. 1999 Jan;45(1):25-32
9894873
Neurology. 1998 Jan;50(1):252-8
9443488
Neurology. 2008 Nov 4;71(19):1506-13
18981372
Neurology. 1994 May;44(5):823-8
8190282
Neurobiol Dis. 2006 May;22(2):388-400
16473015
Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2945-9
17299049
Ann Neurol. 1982 Nov;12(5):425-34
6217782
J Neurol Neurosurg Psychiatry. 2004 Feb;75(2):209-12
14742590
Ann Neurol. 1988 Jun;23(6):541-6
2970247
Nat Med. 2008 Oct;14(10):1097-105
18806802
Hum Mol Genet. 2009 Mar 15;18(6):1006-16
19124532
Hum Mol Genet. 2010 Oct 15;19(20):3919-35
20660112
J Biol Chem. 2010 May 7;285(19):14777-90
20220138
Antioxid Redox Signal. 2007 Oct;9(10):1647-58
17696767
Exp Neurol. 2009 Aug;218(2):286-92
19358844
Brain Res Bull. 2001 Oct-Nov 1;56(3-4):319-29
11719267
Brain. 1990 Oct;113 ( Pt 5):1405-23
2147116
J Neural Transm (Vienna). 2010 Jan;117(1):77-83
19834779
Brain Res Rev. 2009 Jun;61(1):33-48
19394359
J Biol Chem. 2009 Aug 21;284(34):22938-51
19546216
J Biol Chem. 2002 Mar 1;277(9):7466-76
11739372
Mol Cell Biol. 2004 Sep;24(18):8195-209
15340079
J Neurosci. 2008 Mar 12;28(11):2783-92
18337408
Nat Struct Mol Biol. 2009 Apr;16(4):380-9
19270701
Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1638-43
18230723
Hum Mol Genet. 2005 Oct 1;14(19):2871-80
16115812
Trends Mol Med. 2008 Feb;14(2):45-53
18218341
Ann Neurol. 1986 Sep;20(3):296-303
2945510
Annu Rev Neurosci. 2007;30:575-621
17417937
Biol Psychiatry. 1991 Jan 1;29(1):68-81
1825793
Neurology. 1989 Jun;39(6):796-801
2524678
J Biol Chem. 2002 Oct 25;277(43):41032-7
12171927
Brain Pathol. 1999 Jan;9(1):147-63
9989457
Brain Res Rev. 2011 Jun 24;67(1-2):103-18
21145355
J Neurosci. 2009 Jul 15;29(28):9090-103
19605646
Hum Mol Genet. 2006 May 1;15(9):1437-49
16551656
J Alzheimers Dis. 2010;20 Suppl 2:S609-31
20463406
Hum Mol Genet. 2009 Feb 15;18(4):737-52
19039036
Psychiatry Res. 1999 Feb 22;90(1):67-75
10320212
J Bioenerg Biomembr. 2010 Jun;42(3):193-8
20480217
Science. 2003 Apr 18;300(5618):486-9
12702875
Neurology. 1986 Jul;36(7):888-94
2940474
Nat Struct Mol Biol. 2004 Dec;11(12):1215-22
15543156
J Neuropathol Exp Neurol. 1985 Nov;44(6):559-77
2932539
Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19318-23
19050078
Neurology. 2003 Oct 28;61(8):1085-92
14581669
J Biol Chem. 2008 Apr 18;283(16):10992-1003
18258594
Hum Mol Genet. 2007 Nov 1;16(21):2600-15
17704510
Hum Mol Genet. 2010 Jan 1;19(1):65-78
19825844
Hum Mol Genet. 2004 Jul 15;13(14):1407-20
15163634
Nat Rev Genet. 2005 Oct;6(10):766-73
16136077
Arch Neurol. 2001 Feb;58(2):273-8
11176966
EMBO Mol Med. 2010 Dec;2(12):490-503
21069748
J Biol Chem. 2009 May 15;284(20):13843-13855
19279012
J Neurosci Methods. 2004 Jan 15;132(1):101-7
14687679
Biochem Cell Biol. 2006 Dec;84(6):912-7
17215878
Hum Mol Genet. 2007 Feb 15;16(4):391-409
17189290
Neurology. 1997 Feb;48(2):394-9
9040728