Modulation of mitochondrial function by endogenous Zn2+ pools

Stefano L. Sensi, Dien Ton-That, Patrick G. Sullivan, Elizabeth A. Jonas, Kyle R. Gee, Leonard K. Kaczmarek, John H. Weiss

Research output: Contribution to journalArticlepeer-review

357 Scopus citations

Abstract

Recent evidence suggests that intracellular Zn2+ accumulation contributes to the neuronal injury that occurs in epilepsy or ischemia in certain brain regions, including hippocampus, amygdala, and cortex. Although most attention has been given to the vesicular Zn2+ that is released into the synaptic space and may gain entry to postsynaptic neurons, recent studies have highlighted pools of intracellular Zn2+ that are mobilized in response to stimulation. One such Zn2+ pool is likely bound to cytosolic proteins, like metallothioneins. Applying imaging techniques to cultured cortical neurons, this study provides novel evidence for the presence of a mitochondrial pool distinct from the cytosolic protein or ligand-bound pool. These pools can be pharmacologically mobilized largely independently of each other, with Zn2+ release from one resulting in apparent net Zn2+ transfer to the other. Further studies found evidence for complex and potent effects of Zn2+ on isolated brain mitochondria. Submicromolar levels, comparable to those that might occur on strong mobilization of intracellular compartments, induced membrane depolarization (loss of Δψm), increases in currents across the mitochondrial inner membrane as detected by direct patch clamp recording of mitoplasts, increased O2 consumption and decreased reactive oxygen species (ROS) generation, whereas higher levels decreased O2 consumption and increased ROS generation. Finally, strong mobilization of proteinbound Zn2+ appeared to induce partial loss of Δψm, suggesting that movement of Zn2+ between cytosolic and mitochondrial pools might be of functional significance in intact neurons.

Original languageEnglish
Pages (from-to)6157-6162
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number10
DOIs
StatePublished - May 13 2003

ASJC Scopus subject areas

  • General

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