Mitochondrial dysfunction induced by heat stress in cultured rat CNS neurons

Michael G. White, Osama Saleh, Doris Nonner, Ellen F. Barrett, Carlos T. Moraes, John N. Barrett

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Previous work demonstrated that hyperthermia (43°C for 2 h) results in delayed, apoptotic-like death in striatal neuronal cultures. We investigated early changes in mitochondrial function induced by this heat stress. Partial depolarization of the mitochondrial membrane potential (ΔΨm) began about 1 h after the onset of hyperthermia and increased as the stress continued. When the heat stress ended, there was a partial recovery of ΔΨm, followed hours later by a progressive, irreversible depolarization of ΔΨm. During the heat stress, O2 consumption initially increased but after 20-30 min began a progressive, irreversible decline to about one-half the initial rate by the end of the stress. The percentage of oligomycin-insensitive respiration increased during the heat stress, suggesting an increased mitochondrial leak conductance. Analysis using inhibitors and substrates for specific respiratory chain complexes indicated hyperthermia-induced dysfunction at or upstream of complex I. ATP levels remained near normal for ~4 h after the heat stress. Mitochondrial movement along neurites was markedly slowed during and just after the heat stress. The early, persisting mitochondrial dysfunction described here likely contributes to the later (>10 h) caspase activation and neuronal death produced by this heat stress. Consistent with this idea, proton carrier-induced ΔΨm depolarizations comparable in duration to those produced by the heat stress also reduced neuronal viability. Post-stress ΔΨm depolarization and/or delayed neuronal death were modestly reduced/postponed by nicotinamide adenine dinucleotide, a calpain inhibitor, and increased expression of Bcl-xL.

Original languageEnglish (US)
Pages (from-to)2203-2214
Number of pages12
JournalJournal of neurophysiology
Volume108
Issue number8
DOIs
StatePublished - Oct 15 2012

Keywords

  • Apoptosis;neuron
  • ATP
  • Heatstress
  • Hyperthermia
  • Mitochondria
  • Mitochondrial membrane potential
  • Respiration

ASJC Scopus subject areas

  • Physiology
  • Neuroscience(all)

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