title: Mitochondrial dysfunction induced by heat stress in cultured rat CNS neurons.
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 (ΔΨ(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 ΔΨ(m), followed hours later by a progressive, irreversible depolarization of ΔΨ(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 ∼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 ΔΨ(m) depolarizations comparable in duration to those produced by the heat stress also reduced neuronal viability. Post-stress ΔΨ(m) depolarization and/or delayed neuronal death were modestly reduced/postponed by nicotinamide adenine dinucleotide, a calpain inhibitor, and increased expression of Bcl-xL.
authors: Dept. of Physiology and Biophysics, Univ. of Miami Miller School of Medicine, Miami, FL 33101, USA.
authors: Michael G
authors: MG
authors: White
authors: Osama
authors: O
authors: Saleh
authors: Doris
authors: D
authors: Nonner
authors: Ellen F
authors: EF
authors: Barrett
authors: Carlos T
authors: CT
authors: Moraes
authors: John N
authors: JN
authors: Barrett
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D018869:Heat-Shock Response; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009840:Oligomycins; D010100:Oxygen / Q000378:metabolism; D011522:Protons; D051381:Rats; D012119:Respiration
chemical_list: D024101:Mitochondrial Proteins; D009840:Oligomycins; D011522:Protons; D000255:Adenosine Triphosphate; D010100:Oxygen; D002118:Calcium