Repetitive nerve stimulation transiently opens the mitochondrial permeability transition pore in motor nerve terminals of symptomatic mutant SOD1 mice

Khanh T. Nguyen, John N. Barrett, Luis García-Chacón, Gavriel David, Ellen F. Barrett

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Mitochondria in motor nerve terminals temporarily sequester large Ca2+ loads during repetitive stimulation. In wild-type mice this Ca2+ uptake produces a small (<5mV), transient depolarization of the mitochondrial membrane potential (Ψm, motor nerve stimulated at 100Hz for 5s). We demonstrate that this stimulation-induced Ψm depolarization attains much higher amplitudes in motor terminals of symptomatic mice expressing the G93A or G85R mutation of human superoxide dismutase 1 (SOD1), models of familial amyotrophic lateral sclerosis (fALS). These large Ψm depolarizations decayed slowly and incremented with successive stimulus trains. Additional Ψm depolarizations occurred that were not synchronized with stimulation. These large Ψm depolarizations were reduced (a) by cyclosporin A (CsA, 1-2μM), which inhibits opening of the mitochondrial permeability transition pore (mPTP), or (b) by replacing bath Ca2+ with Sr2+, which enters motor terminals and mitochondria but does not support mPTP opening. These results are consistent with the hypothesis that the large Ψm depolarizations evoked by repetitive stimulation in motor terminals of symptomatic fALS mice result from mitochondrial dysfunction that increases the likelihood of transient mPTP opening during Ca2+ influx. Such mPTP openings, a sign of mitochondrial stress, would disrupt motor terminal handling of Ca2+ loads and might thereby contribute to motor terminal degeneration in fALS mice. Ψm depolarizations resembling those in symptomatic fALS mice could be elicited in wild-type mice following a 0.5-1h exposure to diamide (200μM), which produces an oxidative stress, but these depolarizations were not reduced by CsA.

Original languageEnglish (US)
Pages (from-to)381-390
Number of pages10
JournalNeurobiology of Disease
Volume42
Issue number3
DOIs
StatePublished - Jun 2011

Keywords

  • Mitochondria
  • Mitochondrial calcium uptake
  • Mitochondrial membrane potential
  • Mitochondrial permeability transition pore
  • Motor nerve terminal
  • Motor neuron
  • Mouse models of familial amyotrophic lateral sclerosis
  • Oxidative stress
  • Superoxide dismutase 1 G85R
  • Superoxide dismutase 1 G93A

ASJC Scopus subject areas

  • Neurology

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