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Zentrum Physiologie und Pathophysiologie, Universität Göttingen, Humboldtallee 23, 37073 Göttingen, Germany

Motoneurones (MNs) are particularly affected by the inhibition of mitochondrial metabolism, which has been linked to their selective vulnerability during pathophysiological states like hypoxia and amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. To elucidate underlying events, we used sodium cyanide (CN) as a pharmacological inhibitor of complex IV of the mitochondrial respiratory chain (‘chemical hypoxia’) and investigated the cellular response in vulnerable and resistant neurone types. Bath application of 2 mM CN activated TTX-insensitive Na⁺ conductances in vulnerable hypoglossal MNs, which depolarized these MNs by 10.2 ± 1.1 mV and increased their action potential activity. This response was mimicked by sodium azide (2 mM) and largely prevented by preincubation with the antioxidants ascorbic acid (1 mM) and Trolox (750 µM), indicating an involvement of reactive oxygen species (ROS) in the activation mechanism. CN also elevated cytosolic [Ca²⁺] levels through (i) Ca²⁺ release from mitochondria-controlled stores, (ii) significant retardation of cytosolic Ca²⁺ clearance rates, even when cytosolic ATP levels were held constant during whole-cell recording, and (iii) secondary Ca²⁺ influx during elevated firing rates. Blocking mitochondrial ATP production additionally raised cytosolic Ca²⁺ levels and prolonged recovery of Ca²⁺ transients with a delay of 5–6 min. Comparative studies on hypoglossal MNs, facial MNs and dorsal vagal neurones suggested that CN responses were dominated by the activation of K⁺ conductances in resistant neurones, thus reducing excitability during mitochondrial inhibition. In summary, our observations therefore support a model where selective MN vulnerability results from a synergistic accumulation of risk factors, including low cytosolic Ca²⁺ buffering, strong mitochondrial impact on [Ca²⁺]_i, and a mitochondria-controlled increase in electrical excitability during metabolic disturbances.

(Received 25 August 2003; accepted after revision 4 December 2003; first published online 5 December 2003)
Corresponding author B. U. Keller: Centre of Physiology, University of Göttingen, Humboldtallee 23, 37073 Göttingen, Germany. Email: bkeller{at}ukps.gwdg.de

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