Zn2+ inhibits mitochondrial movement in neurons by phosphatidylinositol 3-kinase activation.
Mitochondria have been identified as targets of the neurotoxic actions of zinc, possibly through decreased mitochondrial energy production and increased reactive oxygen species accumulation. It has been hypothesized that impairment of mitochondrial trafficking may be a mechanism of neuronal injury. Here, we report that elevated intraneuronal zinc impairs mitochondrial trafficking. At concentrations just sufficient to cause injury, zinc rapidly inhibited mitochondrial movement without altering morphology. Zinc chelation initially restored movement, but the actions of zinc became insensitive to chelator in <10 min. A search for downstream signaling events revealed that inhibitors of phosphatidylinositol (PI) 3-kinase prevented this zinc effect on movement. Moreover, transient inhibition of PI 3-kinase afforded neuroprotection against zinc-mediated toxicity. These data illustrate a novel mechanism that regulates mitochondrial trafficking in neurons and also suggest that mitochondrial trafficking may be closely coupled to neuronal viability.
Malaiyandi
Latha M
LM
Department of Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Honick
Anthony S
AS
Rintoul
Gordon L
GL
Wang
Qiming J
QJ
Reynolds
Ian J
IJ
D000818:Animals; D002413:Cations, Divalent; D002478:Cells, Cultured; D002712:Chlorides / Q000494:pharmacology / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology*; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology*; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015032:Zinc / Q000494:pharmacology* / Q000502:physiology; D017967:Zinc Compounds / Q000494:pharmacology
D002413:Cations, Divalent; D002712:Chlorides; D017967:Zinc Compounds; C016837:zinc chloride; D019869:Phosphatidylinositol 3-Kinases; D015032:Zinc