title: Accumulation of mitochondrial DNA damage and bioenergetic dysfunction in CSB defective cells.
abstract: Cockayne syndrome (CS) is a complex, progressive disease that involves neurological and developmental impairment and premature aging. The majority of CS patients have mutations in the CSB gene. The CSB protein is involved in multiple DNA repair pathways and CSB mutated cells are sensitive to a broad spectrum of genotoxic agents. We tested the hypothesis that sensitivity to such genotoxins could be mediated by mitochondrial dysfunction as a consequence of the CSB mutation. mtDNA from csb(m/m) mice accumulates oxidative damage including 8-oxoguanine, and cells from this mouse are hypersensitive to the mitochondrial oxidant menadione. Inhibitors of mitochondrial complexes and the glycolysis inhibitor 2-deoxyglucose kill csb(m/m) cells more efficiently than wild-type cells, via a mechanism that does not correlate with mtDNA damage formation. Menadione depletes cellular ATP, and recovery after depletion is slower in csb(m/m) cells. The bioenergetic alteration in csb(m/m) cells parallels the simpler organization of supercomplexes consisting of complexes I, III and IV in addition to partially disassembled complex V in the inner mitochondrial membrane. Exposing wild-type cells to DNA intercalating agents induces complex alterations, suggesting a link between mtDNA integrity, respiratory complexes and mitochondrial function. Thus, mitochondrial dysfunction may play a role in the pathology of CS.
authors.affiliation: Institute of Clinical Biochemistry, Faculty division Rikshospitalet, University of Oslo, Norway.
authors.forename: Pia Ø
authors.initials: PØ
authors.lastname: Osenbroch
authors.forename: Pia
authors.initials: P
authors.lastname: Auk-Emblem
authors.forename: Ruth
authors.initials: R
authors.lastname: Halsne
authors.forename: Janne
authors.initials: J
authors.lastname: Strand
authors.forename: Rune J
authors.initials: RJ
authors.lastname: Forstrøm
authors.forename: Ingrid
authors.initials: I
authors.lastname: van der Pluijm
authors.forename: Lars
authors.initials: L
authors.lastname: Eide
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D003057:Cockayne Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004249:DNA Damage; D004265:DNA Helicases; D045643:DNA Repair Enzymes; D004272:DNA, Mitochondrial / Q000235:genetics*; D004591:Electrophoresis, Polyacrylamide Gel; D004734:Energy Metabolism; D006801:Humans; D018384:Oxidative Stress; D000075223:Poly-ADP-Ribose Binding Proteins
chemical_list: D004272:DNA, Mitochondrial; D000075223:Poly-ADP-Ribose Binding Proteins; D000255:Adenosine Triphosphate; D004265:DNA Helicases; C078673:ERCC6 protein, human; D045643:DNA Repair Enzymes