期刊
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
卷 169, 期 -, 页码 96-110出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jsbmb.2016.03.029
关键词
7-Ketocholesterol; alpha-Tocopherol; Mitochondria; Lipid profile; 158N murine oligodendrocytes
资金
- Italian Ministry of Health, Fondi per Giovani Ricercatori [GR-2008-1145270]
- ASAD (Louhans, France)
- Universite de Bourgogne (Ecole Doctorale Environnements -Sante)
- Regional Council of Bourgogne
- Department of Neurology (CHU de Dijon, France)
- Centre Memoire de Ressources et de Recherche (CHU de Dijon, France)
- Association pour le Developpement des Sciences Neurologiques en Bourgogne (ADSNB, Dijon, France)
- Association Bourguignonne pour les Applications des Sciences de l'Information en Medecine (ABASIM, Dijon, France)
In multiple sclerosis (MS) a process of white matter degradation leading to demyelination is observed. Oxidative stress, inflammation, apoptosis, necrosis and/or autophagy result together into a progressive loss of oligodendrocytes. 7-ketocholesterol (7KC), found increased in the cerebrospinal fluid of MS patients, triggers a rupture of RedOx homeostasis associated with mitochondrial dysfunctions, aptoptosis and autophagy (oxiapoptophagy) in cultured murine oligodendrocytes (158N). alpha-tocopherol is able to mild the alterations induced by 7KC partially restoring the cellular homeostasis. In presence of 7KC, the amount of adherent 158N cells was decreased and oxidative stress was enhanced. An increase of caspase-3 and PARP degradation (evidences of apoptosis), and an increased LC3-II/LC3-I ratio (criterion of autophagy), were detected. These events were associated with a decrease of the mitochondrial membrane potential (Mini) and by a decrease of oxidative phosphorylation revealed by reduced NAD+ and ATP. The cellular lactate was higher while pyruvate, citrate, fumarate, succinate (tricarboxylic acid (TCA) cycle intermediates) were significantly reduced in exposed cells, suggesting that an impairment of mitochondrial respiratory functions could lead to an increase of lactate production and to a reduced amount of ATP and acetyl-CoA available for the anabolic pathways. The concentration of sterol precursors lathosterol, lanosterol and desmosterol were significantly reduced together with satured and unsatured long chain fatty acids (C16:0-C18:0, structural elements of membrane phospholipids). Such reductions were milder with alpha-tocopherol. It is likely that the cell death induced by 7KC is associated with mitochondrial dysfunctions, including alterations of oxidative phosphorylation, which could result from lipid anabolism dysfunctions, especially on TCA cycle intermediates. A better knowledge of mitochondrial associated dysfunctions triggered by 7KC will contribute to bring new information on the demyelination processes which are linked with oxidative stress and lipid peroxidation, especially in MS. (C) 2016 Elsevier Ltd. All rights reserved.
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