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Mitochondrial permeability transition in neuronal damage promoted by Ca 2+ and respiratory chain complex II inhibition
Author(s) -
Maciel Evelise N.,
Kowaltowski Alicia J.,
Schwalm Fábio D.,
Rodrigues Juliana M.,
Souza Diogo O.,
Vercesi Anibal E.,
Wajner Moacir,
Castilho Roger F.
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02565.x
Subject(s) - mitochondrial permeability transition pore , mitochondrion , respiratory chain , malonate , mitochondrial respiratory chain , programmed cell death , biology , respiration , mptp , biochemistry , chemistry , microbiology and biotechnology , apoptosis , endocrinology , anatomy , dopaminergic , dopamine
Changes in mitochondrial integrity, reactive oxygen species release and Ca 2+ 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 Ca 2+ 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 Ca 2+ cycling and absent when mitochondria were pre‐loaded with Ca 2+ or when Ca 2+ 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.