Mitochondrial dysfunction induced by heat stress in cultured rat CNS neurons.

White MG, Saleh O, Nonner D, Barrett EF, Moraes CT, Barrett JN. Mitochondrial dysfunction induced by heat stress in cultured rat CNS neurons. J Neurophysiol 108: 2203-2214, 2012. First published July 25, 2012; doi:10.1152/jn.00638.2011.-Previous work demonstrated that hyperthermia (43 degrees 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 (Delta Psi(m)) 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 Delta Psi(m), followed hours later by a progressive, irreversible depolarization of Delta Psi(m). During the heat stress, O-2 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 similar to 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 Delta Psi(m) depolarizations comparable in duration to those produced by the heat stress also reduced neuronal viability. Post-stress Delta Psi(m) depolarization and/or delayed neuronal death were modestly reduced/postponed by nicotinamide adenine dinucleotide, a calpain inhibitor, and increased expression of Bcl-xL.