Regulation of calcium-induced opening of MPTP by cyclosporin A and rotenone in mitochondria isolated from rat cerebral cortex and cerebellum

Abstract

Mitochondrial damage, particularly opening of mitochondrial permeability transition pore (MPTP), is thought to be critical in ischemic insults and neurodegeneration. The opening of MPTP can induce mitochondrial depolarization and inhibition of ATP synthesis leading to cell death. Therefore, pharmacological inhibition of MPTP may be powerful strategy to improve brain tissue functions in pathological situations. Mitochondria isolated from various brain regions were shown to have different sensitivity to calcium induced MPTP and this may account for different vulnerability to ischemic stress. In this study we investigated mitochondria isolated from different brain areas- cerebral cortex and cerebellum andtested effects of selective inhibitor of MPTPcyclosporin A (CsA) and respiratory chain complex I inhibitor rotenone to calcium induced MPTP measured as calcium retention capacity (CRC). Respiration and CRC were similar in both types of mitochondria. In the presence of 0.5 μM CsA70% increase of CRC of cortical mitochondria was observed, however, 5 μM CsAconcentration was necessary to increase CRC of cerebellum mitochondriaby 70%. We also found that rotenone (1 μM) was more potent than CsA and increased CRC by 100% and 115% in cerebral cortex and cerebellum mitochondria, respectively. Importantly, CsA and rotenone acted synergistically and significantly increased CRC of both, cortical and cerebellum mitochondria (up to 170% and 180%, respectively). These results demonstrated that inhibition of complex I may regulate MPTP and that CsA and rotenone can act in synergistic protective manner against calcium induced opening of MPTP in isolated rat cerebral cortex and cerebellum mitochondria.