title: An altered redox balance mediates the hypersensitivity of Cockayne syndrome primary fibroblasts to oxidative stress.
abstract: Cockayne syndrome (CS) is a rare hereditary multisystem disease characterized by neurological and development impairment, and premature aging. Cockayne syndrome cells are hypersensitive to oxidative stress, but the molecular mechanisms involved remain unresolved. Here we provide the first evidence that primary fibroblasts derived from patients with CS-A and CS-B present an altered redox balance with increased steady-state levels of intracellular reactive oxygen species (ROS) and basal and induced DNA oxidative damage, loss of the mitochondrial membrane potential, and a significant decrease in the rate of basal oxidative phosphorylation. The Na/K-ATPase, a relevant target of oxidative stress, is also affected with reduced transcription in CS fibroblasts and normal protein levels restored upon complementation with wild-type genes. High-resolution magnetic resonance spectroscopy revealed a significantly perturbed metabolic profile in CS-A and CS-B primary fibroblasts compared with normal cells in agreement with increased oxidative stress and alterations in cell bioenergetics. The affected processes include oxidative metabolism, glycolysis, choline phospholipid metabolism, and osmoregulation. The alterations in intracellular ROS content, oxidative DNA damage, and metabolic profile were partially rescued by the addition of an antioxidant in the culture medium suggesting that the continuous oxidative stress that characterizes CS cells plays a causative role in the underlying pathophysiology. The changes of oxidative and energy metabolism offer a clue for the clinical features of patients with CS and provide novel tools valuable for both diagnosis and therapy.
authors.affiliation: Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Via Salaria, Km 29,300, 00016 Monterotondo Stazione, Rome, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Pascucci
authors.forename: Tiziana
authors.initials: T
authors.lastname: Lemma
authors.forename: Egidio
authors.initials: E
authors.lastname: Iorio
authors.forename: Sara
authors.initials: S
authors.lastname: Giovannini
authors.forename: Bruno
authors.initials: B
authors.lastname: Vaz
authors.forename: Ivano
authors.initials: I
authors.lastname: Iavarone
authors.forename: Angelo
authors.initials: A
authors.lastname: Calcagnile
authors.forename: Laura
authors.initials: L
authors.lastname: Narciso
authors.forename: Paolo
authors.initials: P
authors.lastname: Degan
authors.forename: Franca
authors.initials: F
authors.lastname: Podo
authors.forename: Vera
authors.initials: V
authors.lastname: Roginskya
authors.forename: Bratislav M
authors.initials: BM
authors.lastname: Janjic
authors.forename: Bennett
authors.initials: B
authors.lastname: Van Houten
authors.forename: Miria
authors.initials: M
authors.lastname: Stefanini
authors.forename: Eugenia
authors.initials: E
authors.lastname: Dogliotti
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: D'Errico
mesh_terms: D019588:Aging, Premature / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003057:Cockayne Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004249:DNA Damage; D004260:DNA Repair; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress / Q000502:physiology*