Modulation of mitochondrial dysfunction-related oxidative stress in fibroblasts of patients with Leigh syndrome by inhibition of prooxidative p66Shc pathway
| Autor: | Aleksandra Wojtala, Vilma A. Sardão, Maciej Pronicki, Paweł Kowalski, Jerzy Duszyński, Mariusz R. Wieckowski, Joanna Szczepanowska, Agnieszka Karkucinska-Wieckowska |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Src Homology 2 Domain-Containing Transforming Protein 1 Antioxidant medicine.medical_treatment Biology medicine.disease_cause 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Humans Enzyme Inhibitors Protein kinase A Molecular Biology Cells Cultured chemistry.chemical_classification Reactive oxygen species Electron Transport Complex I Cell Biology Fibroblasts Mitochondria Cell biology Oxidative Stress 030104 developmental biology Mitochondrial respiratory chain Biochemistry chemistry Pyrones Mutation Hispidin Molecular Medicine Phosphorylation Leigh Disease Reactive Oxygen Species 030217 neurology & neurosurgery Oxidative stress Intracellular |
| Zdroj: | Mitochondrion. 37:62-79 |
| ISSN: | 1567-7249 |
| Popis: | The mitochondrial respiratory chain, and in particular, complex I, is a major source of reactive oxygen species (ROS) in cells. Elevated levels of ROS are associated with an imbalance between the rate of ROS formation and the capacity of the antioxidant defense system. Increased ROS production may lead to oxidation of DNA, lipids and proteins and thus can affect fundamental cellular processes. The aim of this study was to investigate the magnitude of intracellular oxidative stress in fibroblasts of patients with Leigh syndrome with defined mutations in complex I. Moreover, we hypothesized that activation of the p66Shc protein (phosphorylation of p66Shc at Ser36 by PKCβ), being part of the oxidative stress response pathway, is partially responsible for the increased ROS production in cells with dysfunctional complex I. Characterization of bioenergetic parameters and ROS production showed that the cellular model of Leigh syndrome is described by increased intracellular oxidative stress and oxidative damage to DNA and proteins, which correlate with increased p66Shc phosphorylation at Ser36. Treatment of patient s' fibroblasts with hispidin (an inhibitor of the protein kinase PKCβ), in addition to decreasing ROS production and intracellular oxidative stress, resulted in restoration of complex I activity. |
| Databáze: | OpenAIRE |
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