McManus 2019 Cell Metab: Difference between revisions
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{{Publication | {{Publication | ||
|title=McManus MJ, Picard M, Chen HW, De Haas HJ, Potluri P, Leipzig J, Towheed A, Angelin A, Sengupta P, Morrow RM, Kauffman BA, Vermulst M, Narula J, Wallace DC ( | |title=McManus MJ, Picard M, Chen HW, De Haas HJ, Potluri P, Leipzig J, Towheed A, Angelin A, Sengupta P, Morrow RM, Kauffman BA, Vermulst M, Narula J, Wallace DC (2019) Mitochondrial DNA variation dictates expressivity and progression of nuclear DNA mutations causing cardiomyopathy. Cell Metab 29:78-90. | ||
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30174309 PMID: 30174309] | |info=[https://www.ncbi.nlm.nih.gov/pubmed/30174309 PMID: 30174309] | ||
|authors=McManus MJ, Picard M, Chen HW, De Haas HJ, Potluri P, Leipzig J, Towheed A, Angelin A, Sengupta P, Morrow RM, Kauffman BA, Vermulst M, Narula J, Wallace DC | |authors=McManus MJ, Picard M, Chen HW, De Haas HJ, Potluri P, Leipzig J, Towheed A, Angelin A, Sengupta P, Morrow RM, Kauffman BA, Vermulst M, Narula J, Wallace DC | ||
|year= | |year=2019 | ||
|journal=Cell Metab | |journal=Cell Metab | ||
|abstract=Nuclear-encoded mutations causing metabolic and degenerative diseases have highly variable expressivity. Patients sharing the homozygous mutation (c.523delC) in the adenine nucleotide translocator 1 gene (SLC25A4, ANT1) develop cardiomyopathy that varies from slowly progressive to fulminant. This variability correlates with the mitochondrial DNA (mtDNA) lineage. To confirm that mtDNA variants can modulate the expressivity of nuclear DNA (nDNA)-encoded diseases, we combined in mice the nDNA Slc25a4<sup>-/-</sup> null mutation with a homoplasmic mtDNA ND6<sup>P25L</sup> or COI<sup>V421A</sup> variant. The ND6<sup>P25L</sup> variant significantly increased the severity of cardiomyopathy while the COI<sup>V421A</sup> variant was phenotypically neutral. The adverse Slc25a4<sup>-/-</sup> and ND6<sup>P25L</sup> combination was associated with impaired mitochondrial complex I activity, increased oxidative damage, decreased l-Opa1, altered mitochondrial morphology, sensitization of the mitochondrial permeability transition pore, augmented somatic mtDNA mutation levels, and shortened lifespan. The strikingly different phenotypic effects of these mild mtDNA variants demonstrate that mtDNA can be an important modulator of autosomal disease. | |abstract=Nuclear-encoded mutations causing metabolic and degenerative diseases have highly variable expressivity. Patients sharing the homozygous mutation (c.523delC) in the adenine nucleotide translocator 1 gene (SLC25A4, ANT1) develop cardiomyopathy that varies from slowly progressive to fulminant. This variability correlates with the mitochondrial DNA (mtDNA) lineage. To confirm that mtDNA variants can modulate the expressivity of nuclear DNA (nDNA)-encoded diseases, we combined in mice the nDNA Slc25a4<sup>-/-</sup> null mutation with a homoplasmic mtDNA ND6<sup>P25L</sup> or COI<sup>V421A</sup> variant. The ND6<sup>P25L</sup> variant significantly increased the severity of cardiomyopathy while the COI<sup>V421A</sup> variant was phenotypically neutral. The adverse Slc25a4<sup>-/-</sup> and ND6<sup>P25L</sup> combination was associated with impaired mitochondrial complex I activity, increased oxidative damage, decreased l-Opa1, altered mitochondrial morphology, sensitization of the mitochondrial permeability transition pore, augmented somatic mtDNA mutation levels, and shortened lifespan. The strikingly different phenotypic effects of these mild mtDNA variants demonstrate that mtDNA can be an important modulator of autosomal disease. | ||
|keywords=F(1)F(o)-ATPase, OPA1, Adenine nucleotide translocator, Aging, Cardiomyopathy, Complex I, Complex IV, Mitochondrial DNA, Mitochondrial-nuclear interaction, mtDNA instability | |keywords=F(1)F(o)-ATPase, OPA1, Adenine nucleotide translocator, Aging, Cardiomyopathy, Complex I, Complex IV, Mitochondrial DNA, Mitochondrial-nuclear interaction, mtDNA instability | ||
|editor=[[Plangger M]] | |editor=[[Plangger M]] | ||
|mipnetlab=US PA Philadelphia Wallace DC | |mipnetlab=US PA Philadelphia Wallace DC | ||
}} | }} |
Latest revision as of 12:21, 3 April 2019
McManus MJ, Picard M, Chen HW, De Haas HJ, Potluri P, Leipzig J, Towheed A, Angelin A, Sengupta P, Morrow RM, Kauffman BA, Vermulst M, Narula J, Wallace DC (2019) Mitochondrial DNA variation dictates expressivity and progression of nuclear DNA mutations causing cardiomyopathy. Cell Metab 29:78-90. |
McManus MJ, Picard M, Chen HW, De Haas HJ, Potluri P, Leipzig J, Towheed A, Angelin A, Sengupta P, Morrow RM, Kauffman BA, Vermulst M, Narula J, Wallace DC (2019) Cell Metab
Abstract: Nuclear-encoded mutations causing metabolic and degenerative diseases have highly variable expressivity. Patients sharing the homozygous mutation (c.523delC) in the adenine nucleotide translocator 1 gene (SLC25A4, ANT1) develop cardiomyopathy that varies from slowly progressive to fulminant. This variability correlates with the mitochondrial DNA (mtDNA) lineage. To confirm that mtDNA variants can modulate the expressivity of nuclear DNA (nDNA)-encoded diseases, we combined in mice the nDNA Slc25a4-/- null mutation with a homoplasmic mtDNA ND6P25L or COIV421A variant. The ND6P25L variant significantly increased the severity of cardiomyopathy while the COIV421A variant was phenotypically neutral. The adverse Slc25a4-/- and ND6P25L combination was associated with impaired mitochondrial complex I activity, increased oxidative damage, decreased l-Opa1, altered mitochondrial morphology, sensitization of the mitochondrial permeability transition pore, augmented somatic mtDNA mutation levels, and shortened lifespan. The strikingly different phenotypic effects of these mild mtDNA variants demonstrate that mtDNA can be an important modulator of autosomal disease. โข Keywords: F(1)F(o)-ATPase, OPA1, Adenine nucleotide translocator, Aging, Cardiomyopathy, Complex I, Complex IV, Mitochondrial DNA, Mitochondrial-nuclear interaction, mtDNA instability โข Bioblast editor: Plangger M โข O2k-Network Lab: US PA Philadelphia Wallace DC
Labels: MiParea: Respiration, mtDNA;mt-genetics, nDNA;cell genetics, Genetic knockout;overexpression
Pathology: Myopathy
Organism: Mouse Tissue;cell: Heart Preparation: Isolated mitochondria
Coupling state: LEAK, OXPHOS
Pathway: N, ROX
HRR: Oxygraph-2k
Labels, 2018-09