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Mitochondrial permeability transition in neuronal damage promoted by Ca2+ and respiratory chain complex II inhibition

Evelise N Maciel1, Alicia J Kowaltowski, Fábio D Schwalm

  • 1Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, Brazil.

Journal of Neurochemistry
|August 18, 2004
PubMed

Insights

Mitochondrial complex II inhibition in the central nervous system (CNS) can trigger neuronal cell death through the induction of mitochondrial permeability transition (PT). This process is linked to reactive oxygen species and calcium handling, impacting neurological disorders.

Area of Science:

  • Neuroscience
  • Mitochondrial Biology
  • Biochemistry

Background:

  • Mitochondrial dysfunction, including altered reactive oxygen species (ROS) production and calcium (Ca2+) handling, is implicated in neurological disorders like methylmalonic acidaemia and Huntington's disease.
  • Partial inhibition of mitochondrial respiratory chain complex II is a feature of these conditions.

Purpose of the Study:

  • To investigate the mechanisms by which complex II inhibitors (malonate, methylmalonate, 3-nitropropionate) impact rat brain mitochondrial function and neuronal survival.
  • To elucidate the role of reactive oxygen species and calcium in mediating mitochondrial damage induced by complex II inhibition.

Main Methods:

  • Inhibition of mitochondrial respiration using complex II inhibitors.
  • Assessment of mitochondrial inner membrane permeabilization and mitochondrial permeability transition (PT).
  • Evaluation of methylmalonate's effects on cultured PC12 cells and rat brain slices.

Main Results:

  • Malonate, methylmalonate, and 3-nitropropionate induced mitochondrial inner membrane permeabilization in brain mitochondria at 50% respiratory inhibition, dependent on micromolar Ca2+ concentrations.
  • The observed effect was mediated by ROS and involved mitochondrial PT, as evidenced by prevention with ADP, cyclosporin A, and catalase.
  • In brain mitochondria, PT was stimulated by Ca2+ cycling and prevented by Ca2+ pre-loading or uptake inhibition.
  • Methylmalonate induced neuronal cell death in PC12 cells and striatal slices, independent of energy metabolism impairment, and was attenuated by cyclosporin A and bongkrekate.

Conclusions:

  • Partial inhibition of mitochondrial complex II in the CNS can lead to neuronal cell death.
  • The induction of mitochondrial permeability transition (PT), influenced by ROS and Ca2+ handling, is a key mechanism in this neurotoxicity.
  • These findings provide insights into the pathogenesis of neurological disorders associated with mitochondrial dysfunction.

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