Calleja, Manuel Garesse, Rafael Hernández Sierra, Rosana Kaguni, Laurie S. Matsushima, Yuichi Peralta, Susana Sánchez Martínez, Álvaro Whitworth, Alexander J.
Modeling Pathogenic Mutations of Human Twinkle in Drosophila Suggests an Apoptosis Role in Response to Mitochondrial Defects. [artículo] - PLoS ONE, 2012 2012 - 7(8):e43954.
Formato 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.
PMID: 22952820
Contiene 46 referencias
The 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.
Modeling Pathogenic Mutations of Human Twinkle in Drosophila Suggests an Apoptosis Role in Response to Mitochondrial Defects. [artículo] - PLoS ONE, 2012 2012 - 7(8):e43954.
Formato 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.
PMID: 22952820
Contiene 46 referencias
The 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.
