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

Authors

  • Barbara Pascucci,

    1. Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Via Salaria, Km 29,300, 00016 Monterotondo Stazione, Rome, Italy
    2. Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
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    • These authors equally contributed to this work.

  • Tiziana Lemma,

    1. Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
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    • These authors equally contributed to this work.

  • Egidio Iorio,

    1. Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
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  • Sara Giovannini,

    1. Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
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  • Bruno Vaz,

    1. Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Via Abbiategrasso 207, 27100 Pavia, Italy
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  • Ivano Iavarone,

    1. Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
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  • Angelo Calcagnile,

    1. Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
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  • Laura Narciso,

    1. Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
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  • Paolo Degan,

    1. IRCCS Azienda Ospedaliera Universitaria San Martino – IST – Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi 10, 16132, Genova, Italy
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  • Franca Podo,

    1. Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
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  • Vera Roginskya,

    1. Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
    2. Hillman Cancer Center, The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA
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  • Bratislav M. Janjic,

    1. Hillman Cancer Center, The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA
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  • Bennett Van Houten,

    1. Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
    2. Hillman Cancer Center, The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA
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  • Miria Stefanini,

    1. Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Via Abbiategrasso 207, 27100 Pavia, Italy
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  • Eugenia Dogliotti,

    1. Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
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  • Mariarosaria D’Errico

    1. Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
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Eugenia Dogliotti, Mariarosaria D’Errico, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. Tel.: 0039 06 49902580; fax: 0039 06 49903650; e-mail: eugenia.dogliotti@iss.it;mariarosaria.derrico@iss.it

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.

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