M. Merad-saidoune et al., Overproduction of Cu/Zn-superoxide dismutase or Bcl-2 prevents the brain mitochondrial respiratory dysfunction induced by glutathione depletion, EXP NEUROL, 158(2), 1999, pp. 428-436
Recent work has focused attention on the role of oxidative stress in variou
s acute and chronic neurodegenerative diseases. Low concentrations of the p
owerful antioxidant glutathione (GSH) and impaired brain energy metabolism,
particularly in the substantia nigra, are key features of Parkinson's dise
ase (PD). The main goal of this study was to better characterize the delete
rious effects of brain GSH depletion on mitochondrial function. We depleted
GSH in the brains of newborn wild-type (WT) and transgenic (Tg) mice overp
roducing either human Cu/Zn-superoxide dismutase (h-CuZnSOD) or human Bcl2
(h-Bcl-2), by subcutaneous injection of L-buthionine sulfoximine (BSO), a s
pecific inhibitor of gamma-glutamylcysteine synthetase. GSH was 97% deplete
d in brain homogenates and 90% depleted in brain mitochondria for both WT a
nd Tg mice. This depletion of brain GSH led to a decrease in the activity o
f the GSH-dependent antioxidant enzyme glutathione peroxidase, both in WT a
nd in Tg animals. BSO treatment decreased the activities of respiratory com
plexes I, II, and IV in the brain homogenates of WT mice. BSO-treated h-CuZ
nSOD or h-Bcl-2 Tg mice had no respiratory chain deficiencies. Thus, brain
GSH depletion leads to the impairment of mitochondrial respiratory chain ac
tivity. The protection of mitochondrial respiratory function by overproduct
ion of Bcl-2 may result hom a decrease in the generation of reactive oxygen
species (ROS) or lipid peroxidation. The protection of mitochondria by ove
rproduction of CuZn-SOD is consistent with the involvement of superoxide or
superoxide-derived ROS in the mitochondrial dysfunction caused by brain GS
H depletion. This study demonstrates that the antioxidant balance is critic
al for maintenance of brain mitochondrial function, and its disruption may
contribute to the pathogenesis of PD. (C) 1999 Academic Press.