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Impact of mitochondrial inhibition on excitability and cytosolic Ca 2+ levels in brainstem motoneurones from mouse
Author(s) -
Bergmann Friederike,
Keller Bernhard U.
Publication year - 2004
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2003.053900
Subject(s) - cytosol , mitochondrion , chemistry , sodium cyanide , biophysics , biochemistry , microbiology and biotechnology , medicine , biology , cyanide , enzyme , inorganic chemistry
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 m m 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 m m ) and largely prevented by preincubation with the antioxidants ascorbic acid (1 m m ) and Trolox (750 μ m ), indicating an involvement of reactive oxygen species (ROS) in the activation mechanism. CN also elevated cytosolic [Ca 2+ ] levels through (i) Ca 2+ release from mitochondria‐controlled stores, (ii) significant retardation of cytosolic Ca 2+ clearance rates, even when cytosolic ATP levels were held constant during whole‐cell recording, and (iii) secondary Ca 2+ influx during elevated firing rates. Blocking mitochondrial ATP production additionally raised cytosolic Ca 2+ levels and prolonged recovery of Ca 2+ 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 Ca 2+ buffering, strong mitochondrial impact on [Ca 2+ ] i , and a mitochondria‐controlled increase in electrical excitability during metabolic disturbances.