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Overproduction of Cu/Zn-Superoxide Dismutase or Bcl-2 Prevents the Brain Mitochondrial Respiratory Dysfunction Induced by Glutathione Depletion.

Abstract : Recent work has focused attention on the role of oxidative stress in various acute and chronic neurodegenerative diseases. Low concentrations of the powerful antioxidant glutathione (GSH) and impaired brain energy metabolism, particularly in the substantia nigra, are key features of Parkinson's disease (PD). The main goal of this study was to better characterize the deleterious effects of brain GSH depletion on mitochondrial function. We depleted GSH in the brains of newborn wild-type (WT) and transgenic (Tg) mice overproducing either human Cu/Zn-superoxide dismutase (h-CuZnSOD) or human Bcl2 (h-Bcl-2), by subcutaneous injection of -buthionine sulfoximine (BSO), a specific inhibitor of γ-glutamylcysteine synthetase. GSH was 97% depleted in brain homogenates and 90% depleted in brain mitochondria for both WT and Tg mice. This depletion of brain GSH led to a decrease in the activity of the GSH-dependent antioxidant enzyme glutathione peroxidase, both in WT and in Tg animals. BSO treatment decreased the activities of respiratory complexes I, II, and IV in the brain homogenates of WT mice. BSO-treated h-CuZnSOD or h-Bcl-2 Tg mice had no respiratory chain deficiencies. Thus, brain GSH depletion leads to the impairment of mitochondrial respiratory chain activity. The protection of mitochondrial respiratory function by overproduction of Bcl-2 may result from a decrease in the generation of reactive oxygen species (ROS) or lipid peroxidation. The protection of mitochondria by overproduction of CuZnSOD is consistent with the involvement of superoxide or superoxide-derived ROS in the mitochondrial dysfunction caused by brain GSH depletion. This study demonstrates that the antioxidant balance is critical for maintenance of brain mitochondrial function, and its disruption may contribute to the pathogenesis of PD.
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https://hal-normandie-univ.archives-ouvertes.fr/hal-01762047
Contributor : Université Normandie <>
Submitted on : Monday, April 9, 2018 - 3:52:47 PM
Last modification on : Monday, July 1, 2019 - 3:08:08 PM

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Mérad-Sa\"ıdoune M, Boitier E, Nicole A, Marsac C, Martinou Jc, et al.. Overproduction of Cu/Zn-Superoxide Dismutase or Bcl-2 Prevents the Brain Mitochondrial Respiratory Dysfunction Induced by Glutathione Depletion.. Experimental Neurology, Elsevier, 1999, 158 (2), pp.428-436. ⟨10.1006/exnr.1999.7108⟩. ⟨hal-01762047⟩

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