title: Identification of ataxia-associated mtDNA mutations (m.4052T>C and m.9035T>C) and evaluation of their pathogenicity in transmitochondrial cybrids.
abstract: The potential pathogenicity of two homoplasmic mtDNA point mutations, 9035T>C and 4452T>C, found in a family afflicted with maternally transmitted cognitive developmental delay, learning disability, and progressive ataxia was evaluated using transmitochondrial cybrids. We confirmed that the 4452T>C transition in tRNA(Met) represented a polymorphism; however, 9035T>C conversion in the ATP6 gene was responsible for a defective F(0)-ATPase. Accordingly, mutant cybrids had a reduced oligomycin-sensitive ATP hydrolyzing activity. They had less than half of the steady-state content of ATP and nearly an 8-fold higher basal level of reactive oxygen species (ROS). Mutant cybrids were unable to cope with additional insults, i.e., glucose deprivation or tertiary-butyl hydroperoxide, and they succumbed to either apoptotic or necrotic cell death. Both of these outcomes were prevented by the antioxidants CoQ(10) and vitamin E, suggesting that the abnormally high levels of ROS were the triggers of cell death. In conclusion, the principal metabolic defects, i.e., energy deficiency and ROS burden, resulted from the 9035T>C mutation and could be responsible for the development of clinical symptoms in this family. Furthermore, antioxidant therapy might prove helpful in the management of this disease.
authors.affiliation: Neurogenesis and Brain Repair Group M54, Institute for Biological Sciences, National Research Council Canada, 1200 Montreal Road, Ottawa, Ontario, K1A 0R6, Canada. marianna.sikorska@nrc.ca
authors.forename: Marianna
authors.initials: M
authors.lastname: Sikorska
authors.forename: Jagdeep K
authors.initials: JK
authors.lastname: Sandhu
authors.forename: David K
authors.initials: DK
authors.lastname: Simon
authors.forename: Vimukthi
authors.initials: V
authors.lastname: Pathiraja
authors.forename: Caroline
authors.initials: C
authors.lastname: Sodja
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Maria
authors.initials: M
authors.lastname: Ribecco-Lutkiewicz
authors.forename: Patricia
authors.initials: P
authors.lastname: Lanthier
authors.forename: Henryk
authors.initials: H
authors.lastname: Borowy-Borowski
authors.forename: Adrian
authors.initials: A
authors.lastname: Upton
authors.forename: Sandeep
authors.initials: S
authors.lastname: Raha
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pulst
authors.forename: Mark A
authors.initials: MA
authors.lastname: Tarnopolsky
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D000704:Analysis of Variance; D000975:Antioxidants / Q000494:pharmacology; D001259:Ataxia / Q000150:complications / Q000235:genetics*; D053148:Caspase 3 / Q000378:metabolism; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002675:Child, Preschool; D003072:Cognition Disorders / Q000150:complications / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D004272:DNA, Mitochondrial / Q000235:genetics*; D002658:Developmental Disabilities / Q000150:complications / Q000235:genetics; D005192:Family Health; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005909:Glioblastoma / Q000473:pathology; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000150:complications / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014815:Vitamins / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D014815:Vitamins; D000255:Adenosine Triphosphate; D053148:Caspase 3