title: Deletion of the Complex I Subunit NDUFS4 Adversely Modulates Cellular Differentiation.
abstract: The vast majority of cellular ATP is produced by the oxidative phosphorylation (OXPHOS) system, which comprises the four complexes of the electron transfer chain plus the ATP synthase. Complex I is the largest of the OXPHOS complexes, and mutation of the genes encoding either the subunits or assembly factors of Complex I can result in Complex I deficiency, which is the most common OXPHOS disorder. Mutations in the Complex I gene NDUFS4 lead to Leigh syndrome, which is the most frequent presentation of Complex I deficiency in children presenting with progressive encephalopathy shortly after birth. Symptoms include motor and intellectual retardation, often accompanied by dystonia, ataxia, and growth retardation, and most patients die by 3 years of age. To understand the origins of this disease, we have generated a series of mouse embryonic stem cell lines from blastocysts that were wild type, heterozygous, and homozygous for the deletion of the Ndufs4 gene. We have demonstrated their pluripotency and potential to differentiate into all cell types of the body. Although the loss of Ndufs4 did not affect the stability of the mitochondrial and nuclear genomes, there were significant differences in patterns of chromosomal gene expression following both spontaneous differentiation and directed neural differentiation into astrocytes. The defect also affected the potential of the cells to generate beating embryoid bodies. These outcomes demonstrate that defects associated with Complex I deficiency affect early gene expression patterns, which escalate during early and later stages of differentiation and are mediated by the defect and not other chromosomal or mitochondrial DNA defects.
authors.affiliation: 1 Centre for Genetic Diseases, Hudson Institute of Medical Research , Clayton, Australia .|2 Department of Molecular and Translational Science, Monash University , Clayton, Australia .
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Johnson
authors.affiliation: 1 Centre for Genetic Diseases, Hudson Institute of Medical Research , Clayton, Australia .|2 Department of Molecular and Translational Science, Monash University , Clayton, Australia .
authors.forename: William
authors.initials: W
authors.lastname: Lee
authors.affiliation: 3 Murdoch Childrens Research Institute, Royal Children's Hospital , Melbourne, Australia .|4 Department of Pediatrics, University of Melbourne , Melbourne, Australia .
authors.forename: Ann E
authors.initials: AE
authors.lastname: Frazier
authors.affiliation: 1 Centre for Genetic Diseases, Hudson Institute of Medical Research , Clayton, Australia .|2 Department of Molecular and Translational Science, Monash University , Clayton, Australia .
authors.forename: Vijesh
authors.initials: V
authors.lastname: Vaghjiani
authors.affiliation: 3 Murdoch Childrens Research Institute, Royal Children's Hospital , Melbourne, Australia .
authors.forename: Adrienne
authors.initials: A
authors.lastname: Laskowski
authors.affiliation: 5 Research School of Engineering, Australian National University , Canberra, Australia .
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Rodriguez
authors.affiliation: 1 Centre for Genetic Diseases, Hudson Institute of Medical Research , Clayton, Australia .|2 Department of Molecular and Translational Science, Monash University , Clayton, Australia .
authors.forename: Gael L
authors.initials: GL
authors.lastname: Cagnone
authors.affiliation: 1 Centre for Genetic Diseases, Hudson Institute of Medical Research , Clayton, Australia .|2 Department of Molecular and Translational Science, Monash University , Clayton, Australia .
authors.forename: Matthew
authors.initials: M
authors.lastname: McKenzie
authors.affiliation: 1 Centre for Genetic Diseases, Hudson Institute of Medical Research , Clayton, Australia .|2 Department of Molecular and Translational Science, Monash University , Clayton, Australia .
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: White
authors.affiliation: 5 Research School of Engineering, Australian National University , Canberra, Australia .
authors.forename: David R
authors.initials: DR
authors.lastname: Nisbet
authors.affiliation: 3 Murdoch Childrens Research Institute, Royal Children's Hospital , Melbourne, Australia .|4 Department of Pediatrics, University of Melbourne , Melbourne, Australia .
authors.forename: David R
authors.initials: DR
authors.lastname: Thorburn
authors.affiliation: 1 Centre for Genetic Diseases, Hudson Institute of Medical Research , Clayton, Australia .|2 Department of Molecular and Translational Science, Monash University , Clayton, Australia .
authors.forename: Justin C
authors.initials: JC
authors.lastname: St John
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000378:metabolism; D002460:Cell Line; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D007888:Leigh Disease / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D055495:Neurogenesis; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism
chemical_list: C534449:Ndufs4 protein, mouse; D042967:Electron Transport Complex I