title: The m.3243A>G mtDNA mutation is pathogenic in an in vitro model of the human blood brain barrier.
abstract: MELAS is a common mitochondrial disease frequently associated with the m.3243A>G point mutation in the tRNA(Leu(UUR)) of mitochondrial DNA and characterized by stroke-like episodes with vasogenic edema and lactic acidosis. The pathogenic mechanism of stroke and brain edema is not known. Alterations in the blood brain barrier (BBB) caused by respiratory chain defects in the cortical microvessels could explain the pathogenesis. To test this hypothesis we developed a tissue culture model of the human BBB. The MELAS mutation was introduced into immortalized brain capillary endothelial cells and astrocytes. Respiratory chain activity and transendothelial electrical resistance, TEER was measured. Severe defects of respiratory chain complex I and IV activities, and a moderate deficiency of complex II activity in cells harboring the MELAS mutation were associated with low TEER, indicating that the integrity of the BBB was compromised. These data support our hypothesis that respiratory chain defects in the components of the BBB cause changes in permeability.
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY 10032, United States. mmd2@columbia.edu
authors.forename: Mercy M
authors.initials: MM
authors.lastname: Davidson
authors.forename: Winsome F
authors.initials: WF
authors.lastname: Walker
authors.forename: Evelyn
authors.initials: E
authors.lastname: Hernandez-Rosa
mesh_terms: D001253:Astrocytes / Q000502:physiology*; D001812:Blood-Brain Barrier / Q000502:physiology*; D018929:Cell Culture Techniques / Q000379:methods; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000235:genetics*; D017097:Electric Impedance; D004579:Electron Transport / Q000502:physiology; D042783:Endothelial Cells / Q000502:physiology*; D006801:Humans; D017241:MELAS Syndrome / Q000235:genetics; D010539:Permeability; D017354:Point Mutation; D012356:RNA, Transfer, Leu / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D012356:RNA, Transfer, Leu
references.citation: J Neurosci Res. 1999 Feb 1;55(3):382-93
references.pmid: 10348669
references.citation: Neuroradiology. 2000 Sep;42(9):651-6
references.pmid: 11071437
references.citation: Free Radic Biol Med. 1999 Sep;27(5-6):667-72
references.pmid: 10490287
references.citation: Acta Neurol Scand. 2007 Jul;116(1):1-14
references.pmid: 17587249
references.citation: Neuropathol Appl Neurobiol. 2006 Aug;32(4):359-73
references.pmid: 16866982
references.citation: Biochem Biophys Res Commun. 1999 Dec 9;266(1):179-86
references.pmid: 10581186
references.citation: Biochem J. 2002 Apr 15;363(Pt 2):321-7
references.pmid: 11931660
references.citation: Neurobiol Dis. 2008 Nov;32(2):200-19
references.pmid: 18790057
references.citation: Cancer Res. 2006 May 1;66(9):4566-73
references.pmid: 16651406
references.citation: Cancer Res. 2007 Jun 1;67(11):5239-47
references.pmid: 17545603
references.citation: Brain Res. 2001 Jun 15;904(1):20-30
references.pmid: 11516408
references.citation: Acta Neurochir Suppl (Wien). 1994;60:136-8
references.pmid: 7976526
references.citation: Neuroreport. 2001 May 25;12(7):1329-34
references.pmid: 11388405
references.citation: Oncogene. 2003 Feb 27;22(8):1164-80
references.pmid: 12606943
references.citation: Ann Neurol. 1991 Jun;29(6):601-5
references.pmid: 1892363
references.citation: FASEB J. 2005 Nov;19(13):1872-4
references.pmid: 16141364
references.citation: Diabetes Res Clin Pract. 2001 Dec;54 Suppl 2:S45-56
references.pmid: 11733109
references.citation: Biochem Biophys Res Commun. 1997 Oct 9;239(1):139-45
references.pmid: 9345284
references.citation: Ann N Y Acad Sci. 2008 Oct;1142:133-58
references.pmid: 18990125
references.citation: Brain Res. 2000 Jan 10;852(2):374-82
references.pmid: 10678765
references.citation: Neurology. 2004 Apr 27;62(8):1297-302
references.pmid: 15111665
references.citation: Acta Neurochir Suppl. 1997;70:62-4
references.pmid: 9416279
references.citation: Eur J Hum Genet. 2002 May;10(5):289-91
references.pmid: 12082502
references.citation: J Mol Cell Cardiol. 2005 Jul;39(1):133-47
references.pmid: 15913645
references.citation: Mol Cell Biol. 1992 Feb;12(2):480-90
references.pmid: 1732728
references.citation: Ann Neurol. 1977 May;1(5):409-17
references.pmid: 617259
references.citation: Genet Mol Res. 2008 Oct 14;7(4):1054-62
references.pmid: 19048484
references.citation: Semin Cell Dev Biol. 2001 Dec;12(6):429-39
references.pmid: 11735377
references.citation: Neurology. 1999 Dec 10;53(9):2182-4
references.pmid: 10599803
references.citation: Biochem J. 2004 Dec 1;384(Pt 2):287-93
references.pmid: 15324306
references.citation: Trends Biochem Sci. 2000 Oct;25(10):502-8
references.pmid: 11050436
references.citation: Brain Pathol. 1992 Apr;2(2):113-9
references.pmid: 1341952