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 language | English (US) |
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Pages (from-to) | 2203-2214 |
Number of pages | 12 |
Journal | Journal of neurophysiology |
Volume | 108 |
Issue number | 8 |
DOIs | |
State | Published - Oct 15 2012 |
Keywords
- Apoptosis;neuron
- ATP
- Heatstress
- Hyperthermia
- Mitochondria
- Mitochondrial membrane potential
- Respiration
ASJC Scopus subject areas
- Physiology
- Neuroscience(all)