Coenzyme Q cytoprotective mechanisms for mitochondrial complex I cytopathies involves NAD(P)H: Quinone oxidoreductase 1(NQO1)

被引:68
作者
Chan, TS
Teng, S
Wilson, JX
Galati, G
Khan, S
O'Brien, PJ
机构
[1] Univ Toronto, Fac Pharm, Toronto, ON M5S 2S2, Canada
[2] Univ Western Ontario, Dept Physiol, London, ON N6A 5C1, Canada
[3] Univ Toronto, Dept Pharmacol, Toronto, ON, Canada
关键词
coenzyme Q; mitochondrial complex I; Parkinson's disease; cytopathies;
D O I
10.1080/10715760290021270
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The commonest mitochondrial diseases are probably those impairing the function of complex I of the respiratory electron transport chain. Such complex I impairment may contribute to various neurodegenerative disorders e.g. Parkinson's disease. In the following, using hepatocytes as a model cell, we have shown for the first time that the cytotoxicity caused by complex I inhibition by rotenone but not that caused by complex III inhibition by antimycin can be prevented by coenzyme Q (CoQ(1)) or menadione. Furthermore, complex I inhibitor cytotoxicity was associated with the collapse of the mitochondrial membrane potential and reactive oxygen species (ROS) formation. ROS scavengers or inhibitors of the mitochondrial permeability transition prevented cytotoxicity The CoQ(1) cytoprotective mechanism required CoQ(1) reduction by DT-diaphorase (NQO(1)). Furthermore, the mitochondrial membrane potential and ATIP levels were restored at low CoQ(1) concentrations (5 muM). This suggests that the CoQ(1)H(2) formed by NQO(1) reduced complex III and acted as an electron bypass of the rotenone block. However cytoprotection still occurred at higher CoQ(1) concentrations (>10 muM), which were less effective at restoring ATP levels but readily restored the cellular cytosolic redox potential (i.e. lactate: pyruvate ratio) and prevented ROS formation. This suggests that CoQ(1) or menadione cytoprotection also involves the NQO(1) catalysed reoxidation of NADH that accumulates as a result of complex I inhibition. The CoQ(1)H(2) formed would then also act as a ROS scavenger.
引用
收藏
页码:421 / 427
页数:7
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