Zinc causes loss of membrane potential and elevates reactive oxygen species in rat brain mitochondria.
Emerging evidence suggests that Zn2+ may impair neuronal metabolism. We examined how Zn2+ affects the activity of isolated brain mitochondria fueled with glutamate + malate, succinate or glycerol 3-phosphate. Submicromolar levels of Zn2+ dissipated membrane potential and inhibited oxygen utilization in all three substrate conditions. Zn(2+)-induced depolarization was reversed by the membrane-impermeant metal chelator, EGTA, and was inhibited by uniporter blockade. Cyclosporin A did not block Zn(2+)-induced depolarization. Added Zn2+ increased accumulation of reactive oxygen species (ROS) in glutamate + malate or glycerol 3-phosphate conditions, but inhibited succinate-supported ROS accumulation. These results show that Zn2+ blocks mitochondrial function in all physiologically relevant substrate conditions.
Dineley
Kirk E
KE
Department of Pharmacology, University of Pittsburgh, W1351 Biomedical Science Tower, Pittsburgh, PA 15261, USA.
Richards
Lauren L
LL
Votyakova
Tatyana V
TV
Reynolds
Ian J
IJ
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D004579:Electron Transport / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D005994:Glycerophosphates / Q000378:metabolism; D066298:In Vitro Techniques; D008293:Malates / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D008959:Models, Neurological; D009410:Nerve Degeneration / Q000209:etiology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019802:Succinic Acid / Q000378:metabolism; D015032:Zinc / Q000378:metabolism / Q000494:pharmacology*
D015220:Calcium Channels; D002614:Chelating Agents; D005994:Glycerophosphates; D008293:Malates; D017382:Reactive Oxygen Species; C034703:mitochondrial calcium uniporter; D018698:Glutamic Acid; D004533:Egtazic Acid; C030298:malic acid; C029620:alpha-glycerophosphoric acid; D019802:Succinic Acid; D015032:Zinc