Zinc inhibition of cellular energy production: implications for mitochondria and neurodegeneration

Abstract

An increasing body of evidence suggests that high intracellular free zinc promotes neuronal death by inhibiting cellular energy production. A number of targets have been postulated, including complexes of the mitochondrial electron transport chain, components of the tricarboxylic acid cycle, and enzymes of glycolysis. Consequences of cellular zinc overload may include increased cellular reactive oxygen species (ROS) production, loss of mitochondrial membrane potential, and reduced cellular ATP levels. Additionally, zinc toxicity might involve zinc uptake by mitochondria and zinc induction of mitochondrial permeability transition. The present review discusses these processes with special emphasis on their potential involvement in brain injury. Keywords: electron transport chain, glycolysis, metallothionein, permeability transition, reactive oxygen species, tricarboxylic acid cycle. Interest in Zn2+ -mediated brain injury is motivated by evidence implicating Zn 2+ as a neurotoxin in models of stroke, epilepsy, mechanical trauma, and Alzheimer's disease (Choi and Koh 1998). The precise mechanism of cytotoxicity is unknown, but emerging evidence suggests that Zn 2+ kills neurons through the inhibition of ATP synthesis (Weiss et al. 2000). The notion that Zn 2+ affects energy production is admittedly not a new one; indeed, investigators revealed that Zn 2+ impedes mitochondrial function very soon after mitochondria themselves could be properly studied (Hunter and Ford 1955). There has, however, been a resurgence of interest in this general area due to key advances over the last decade. First, a number of seminal reports have allowed a far better understanding of how zinc is regulated under physiological conditions and how disturbances in zinc homeostasis can lead to neuronal injury. Second, neuroscientists have greatly clarified how energy-producing systems such as mitochondria participate in the events leading to neuronal death. Consequently, investigators are now well positioned to explore the impact of zinc on cellular energy production, and how these events may be related to neurodegeneration. This topic is the principal concern of the present review. Initially, we assess data suggesting that zinc interferes with glycolysis, the tricarboxylic acid cycle (TCA), and the mitochondrial electron transport chain. Several related issues also bear consideration, such as mitochondrial generation of reactive oxygen species (ROS) and possible induction of mitochondrial permeability transition (MPT). We then discuss mitochondrial transport of Zn 2+ and possible regulation of metabolism by the metallothionein family of zinc binding proteins. Finally, we examine approaches used in the determination of intracellular free zinc concentrations, which is a critical component of any hypothesis concerning the mechanism of zinc toxicity. More expansive treatments of the neurobiology of Zn 2+ are cited herein. Zinc in the brainZinc is abundant in the brain with levels at 200 ng/mg protein. As suggested by Frederickson (1989), ...

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