000			03185na a2200325 4500
003			PC8380
005			20210625062808.0
008			130622s2012 xxx||||| |||| 00| 0 eng d
040			_cH12O
041			_aeng
100			_aCalleja, Manuel
100			_9862 _aGaresse, Rafael _eInstituto de Investigación i+12
100			_aHernández Sierra, Rosana _92143 _eInstituto de Investigación I+12
100			_aKaguni, Laurie S.
100			_aMatsushima, Yuichi
100			_aPeralta, Susana _92144 _eInstituto de Investigación i+12
100			_aSánchez Martínez, Álvaro _92145 _eInstituto de Investigación i+12
100			_aWhitworth, Alexander J.
245	o	o	_aModeling Pathogenic Mutations of Human Twinkle in Drosophila Suggests an Apoptosis Role in Response to Mitochondrial Defects. _h[artículo]
260			_bPLoS ONE, _c2012
260			_c2012
300			_a7(8):e43954.
500			_aFormato Vancouver: Sánchez-Martínez A, Calleja M, Peralta S, Matsushima Y, Hernández-Sierra R, Whitworth AJ et al. Modeling pathogenic mutations of human twinkle in Drosophila suggests an apoptosis role in response to mitochondrial defects. PLoS One. 2012;7(8):e43954.
501			_aPMID: 22952820
504			_aContiene 46 referencias
520			_aThe human gene C10orf2 encodes the mitochondrial replicative DNA helicase Twinkle, mutations of which are responsible for a significant fraction of cases of autosomal dominant progressive external ophthalmoplegia (adPEO), a human mitochondrial disease caused by defects in intergenomic communication. We report the analysis of orthologous mutations in the Drosophila melanogaster mitochondrial DNA (mtDNA) helicase gene, d-mtDNA helicase. Increased expression of wild type d-mtDNA helicase using the UAS-GAL4 system leads to an increase in mtDNA copy number throughout adult life without any noteworthy phenotype, whereas overexpression of d-mtDNA helicase containing the K388A mutation in the helicase active site results in a severe depletion of mtDNA and a lethal phenotype. Overexpression of two d-mtDNA helicase variants equivalent to two human adPEO mutations shows differential effects. The A442P mutation exhibits a dominant negative effect similar to that of the active site mutant. In contrast, overexpression of d-mtDNA helicase containing the W441C mutation results in a slight decrease in mtDNA copy number during the third instar larval stage, and a moderate decrease in life span in the adult population. Overexpression of d-mtDNA helicase containing either the K388A or A442P mutations causes a mitochondrial oxidative phosphorylation (OXPHOS) defect that significantly reduces cell proliferation. The mitochondrial impairment caused by these mutations promotes apoptosis, arguing that mitochondria regulate programmed cell death in Drosophila. Our study of d-mtDNA helicase overexpression provides a tractable Drosophila model for understanding the cellular and molecular effects of human adPEO mutations.
710			_9625 _aInstituto de Investigación imas12
856			_uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3429445/pdf/pone.0043954.pdf _yAcceso libre
942			_n0 _2ddc _cART
999			_c8380 _d8380