Mitochondrial permeability transition in neuronal damage promoted by Ca2+ and respiratory chain complex II inhibition.
Changes in mitochondrial integrity, reactive oxygen species release and Ca2+ handling are proposed to be involved in the pathogenesis of many neurological disorders including methylmalonic acidaemia and Huntington's disease, which exhibit partial mitochondrial respiratory inhibition. In this report, we studied the mechanisms by which the respiratory chain complex II inhibitors malonate, methylmalonate and 3-nitropropionate affect rat brain mitochondrial function and neuronal survival. All three compounds, at concentrations which inhibit respiration by 50%, induced mitochondrial inner membrane permeabilization when in the presence of micromolar Ca2+ concentrations. ADP, cyclosporin A and catalase prevented or delayed this effect, indicating it is mediated by reactive oxygen species and mitochondrial permeability transition (PT). PT induced by malonate was also present in mitochondria isolated from liver and kidney, but required more significant respiratory inhibition. In brain, PT promoted by complex II inhibition was stimulated by increasing Ca2+ cycling and absent when mitochondria were pre-loaded with Ca2+ or when Ca2+ uptake was prevented. In addition to isolated mitochondria, we determined the effect of methylmalonate on cultured PC12 cells and freshly prepared rat brain slices. Methylmalonate promoted cell death in striatal slices and PC12 cells, in a manner attenuated by cyclosporin A and bongkrekate, and unrelated to impairment of energy metabolism. We propose that under conditions in which mitochondrial complex II is partially inhibited in the CNS, neuronal cell death involves the induction of PT.
Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, Brazil.
Evelise N
EN
Maciel
Alicia J
AJ
Kowaltowski
Fábio D
FD
Schwalm
Juliana M
JM
Rodrigues
Diogo O
DO
Souza
Anibal E
AE
Vercesi
Moacir
M
Wajner
Roger F
RF
Castilho
D000818:Animals; D000968:Antimycin A / Q000031:analogs & derivatives* / Q000494:pharmacology; D001865:Bongkrekic Acid / Q000494:pharmacology; D001921:Brain / Q000166:cytology*; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology*; D002374:Catalase / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D003524:Cyclosporins / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D007476:Ionophores / Q000494:pharmacology; D008314:Malonates / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D008764:Methylmalonic Acid / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D009574:Nitro Compounds; D010101:Oxygen Consumption / Q000187:drug effects; D016716:PC12 Cells; D010539:Permeability / Q000187:drug effects; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D012402:Rotenone / Q000494:pharmacology; D016559:Tacrolimus / Q000494:pharmacology; D013778:Tetrazolium Salts; D013844:Thiazoles; D014475:Uncoupling Agents / Q000494:pharmacology
D003524:Cyclosporins; D004791:Enzyme Inhibitors; D007476:Ionophores; D008314:Malonates; D009574:Nitro Compounds; D011422:Propionates; D013778:Tetrazolium Salts; D013844:Thiazoles; D014475:Uncoupling Agents; C478189:respiratory complex II; D012402:Rotenone; D001865:Bongkrekic Acid; C032456:antimycin; D000001:Calcimycin; D009249:NADP; D000968:Antimycin A; D008764:Methylmalonic Acid; C030290:malonic acid; D002374:Catalase; D042963:Electron Transport Complex II; C022616:thiazolyl blue; C015392:3-nitropropionic acid; D002118:Calcium; D016559:Tacrolimus