Seizure-dependent modulation of mitochondrial oxidative phosphorylation in rat hippocampus.
Mitochondrial function is a key determinant of both excitability and viability of neurons. Here, we demonstrate seizure-dependent changes in mitochondrial oxidative phosphorylation in the epileptic rat hippocampus. The intense pathological neuronal activity in pilocarpine-treated rats exhibiting spontaneous seizures resulted in a selective decline of the activities of NADH-CoQ oxidoreductase (complex I of the respiratory chain) and cytochrome c oxidase (complex IV of respiratory chain) in the CA3 and CA1 hippocampal pyramidal subfields. In line with these findings, high-resolution respirometry revealed an increased flux control of complex I on respiration in the CA1 and CA3 subfields and decreased maximal respiration rates in the more severely affected CA3 subfield. Imaging of mitochondrial membrane potential using rhodamine 123 showed a lowered mitochondrial membrane potential in both pyramidal subfields. In contrast to the CA1 and CA3 subfields, mitochondrial oxidative phosphorylation was unaltered in the dentate gyrus and the parahippocampal gyrus. The changes of oxidative phosphorylation in the epileptic rat hippocampus cannot be attributed to oxidative enzyme modifications but are very likely related to a decrease in mitochondrial DNA copy number as shown in the more severely affected CA3 subfield and in cultured PC12 cells partially depleted of mitochondrial DNA. Thus, our results demonstrate that seizure activity downregulates the expression of mitochondrial-encoded enzymes of oxidative phosphorylation. This mechanism could be invoked during diverse forms of pathological neuronal activity and could severely affect both excitability and viability of hippocampal pyramidal neurons.
Kudin
Alexei P
AP
Department of Epileptology, University of Bonn Medical Centre, Sigmund-Freud-Str. 25, D-53105 Bonn, Germany.
Kudina
Tatiana A
TA
Seyfried
Jan
J
Vielhaber
Stefan
S
Beck
Heinz
H
Elger
Christian E
CE
Kunz
Wolfram S
WS
D000818:Animals; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002908:Chronic Disease; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D042967:Electron Transport Complex I; D003576:Electron Transport Complex IV / Q000378:metabolism; D004827:Epilepsy / Q000378:metabolism* / Q000503:physiopathology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D018721:Muscarinic Agonists / Q000494:pharmacology; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D009924:Organ Culture Techniques; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010862:Pilocarpine / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013385:Succinate Dehydrogenase / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D004272:DNA, Mitochondrial; D018721:Muscarinic Agonists; D010862:Pilocarpine; D013385:Succinate Dehydrogenase; D009247:NADH, NADPH Oxidoreductases; D003576:Electron Transport Complex IV; D042967:Electron Transport Complex I