title: Induction of mitochondrial oxidative stress in astrocytes by nitric oxide precedes disruption of energy metabolism.
abstract: Inhibition of the mitochondrial electron transport chain (ETC) ultimately limits ATP production and depletes cellular ATP. However, the individual complexes of the ETC in brain mitochondria need to be inhibited by approximately 50% before causing significant depression of ATP synthesis. Moreover, the ETC is the key site for the production of intracellular reactive oxygen species (ROS) and inhibition of one or more of the complexes of the ETC may increase the rate of mitochondrial ROS generation. We asked whether partial inhibition of the ETC, to a degree insufficient to perturb oxidative phosphorylation, might nonetheless induce ROS production. Chronic increase in mitochondrial ROS might then cause oxidative damage to the ETC sufficient to produce prolonged changes in ETC function and so compound the defect. We show that the exposure of astrocytes in culture to low concentrations of nitric oxide (NO) induces an increased rate of O2*- generation that outlasts the presence of NO. No effect was seen on oxygen consumption, lactate or ATP content over the 4-6 h that the cells were exposed to NO. These data suggest that partial ETC inhibition by NO may initially cause oxidative stress rather than ATP depletion, and this may subsequently induce irreversible changes in ETC function providing the basis for a cycle of damage.
authors.affiliation: Miriam Marks Division of Neurochemistry, Institute of Neurology, Department of Biology, University College London, London, UK. j.jacobson@ucl.ac.uk
authors.forename: Jake
authors.initials: J
authors.lastname: Jacobson
authors.forename: Michael R
authors.initials: MR
authors.lastname: Duchen
authors.forename: John
authors.initials: J
authors.lastname: Hothersall
authors.forename: John B
authors.initials: JB
authors.lastname: Clark
authors.forename: Simon J R
authors.initials: SJ
authors.lastname: Heales
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000166:cytology; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003300:Copper / Q000378:metabolism; D004579:Electron Transport / Q000187:drug effects; D003576:Electron Transport Complex IV / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D005246:Feedback / Q000502:physiology; D006418:Heme / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D019344:Lactic Acid / Q000096:biosynthesis; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D009243:NAD / Q000378:metabolism; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism
chemical_list: D020030:Nitric Oxide Donors; D009243:NAD; D013481:Superoxides; D009569:Nitric Oxide; D019344:Lactic Acid; D006418:Heme; D003300:Copper; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV