An altered redox balance mediates the hypersensitivity of Cockayne syndrome primary fibroblasts to oxidative stress

Aging Cell

Barbara Pascucci⁶  Tiziana Lemma⁵  Egidio Iorio²  Sara Giovannini⁵  Bruno Vaz⁴  Ivano Iavarone⁵  Angelo Calcagnile⁵  Laura Narciso⁵  Paolo Degan⁷  Franca Podo²  Vera Roginskya³  Bratislav M. Janjic¹  Bennett Van Houten³  Miria Stefanini⁴  Eugenia Dogliotti⁵ 

[1] Hillman Cancer Center, The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA;Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy;Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA;Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Via Abbiategrasso 207, 27100 Pavia, Italy;Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy;Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Via Salaria, Km 29,300, 00016 Monterotondo Stazione, Rome, Italy;IRCCS Azienda Ospedaliera Universitaria San Martino – IST – Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi 10, 16132, Genova, Italy

关键词: Cockayne syndrome;    DNA oxidation;    mitochondrial alteration;    oxidative metabolism;    oxidative phosphorylation;    ROS levels;   

DOI  :  10.1111/j.1474-9726.2012.00815.x

来源: Wiley

【 摘 要 】

Summary

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.

【 授权许可】

Unknown   
© 2012 The Authors. Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland