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The Journal of Neuroscience, March 15, 2000, 20(6):2094-2103

Exacerbated Responses to Oxidative Stress by an Na⁺ Load in Isolated Nerve Terminals: the Role of ATP Depletion and Rise of [Ca²⁺]_i

Christos Chinopoulos, Laszlo Tretter, Adrienn Rozsa, and Vera Adam-Vizi

Department of Medical Biochemistry, Neurochemical Group, Semmelweis University of Medicine, Budapest H-1444, Hungary

We have explored the consequences of a [Na⁺]_i load and oxidative stress in isolated nerve terminals. The Na⁺ load was achieved by veratridine (5-40 µM), which allows Na⁺ entry via a voltage-operated Na⁺ channel, and oxidative stress was induced by hydrogen peroxide (0.1-0.5 mM). Remarkably, neither the [Na⁺]_i load nor exposure to H₂O₂ had any major effect on [Ca²⁺]_i, mitochondrial membrane potential (m), or ATP level. However, the combination of an Na⁺ load and oxidative stress caused ATP depletion, a collapse of m, and a progressive deregulation of [Ca²⁺]_i and [Na⁺]_i homeostasis. The decrease in the ATP level was unrelated to an increase in [Ca²⁺]_i and paralleled the rise in [Na⁺]_i. The loss of m was prevented in the absence of Ca²⁺ but unaltered in the presence of cyclosporin A. We conclude that the increased ATP consumption by the Na,K-ATPase that results from a modest [Na⁺]_i load places an additional demand on mitochondria metabolically compromised by an oxidative stress, which are unable to produce a sufficient amount of ATP to fuel the ATP-driven ion pumps. This results in a deregulation of [Na⁺]_i and [Ca²⁺]_i, and as a result of the latter, collapse of m. The vicious cycle generated in the combined presence of Na⁺ load and oxidative stress could be an important factor in the neuronal injury produced by ischemia or excitotoxicity, in which the oxidative insult is superimposed on a disturbed Na⁺ homeostasis.

Key words: oxidative stress; Na⁺ load; mitochondrial membrane potential; ATP depletion; Na⁺ deregulation; Ca²⁺ deregulation

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Copyright © 2000 Society for Neuroscience  0270-6474/00/2062094-10$05.00/0

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