Cyclosporin A-insensitive permeability transition in brain mitochondria - Inhibition by 2-aminoethoxydiphenyl borate

Chinopoulos, Christos and Starkov, Anatoly A. and Fiskum, G. (2003) Cyclosporin A-insensitive permeability transition in brain mitochondria - Inhibition by 2-aminoethoxydiphenyl borate. JOURNAL OF BIOLOGICAL CHEMISTRY, 278 (30). pp. 27382-27389. ISSN 0021-9258

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Abstract

The mitochondrial permeability transition pore (PTP) may operate as a physiological Ca 2 � release mechanism and also contribute to mitochondrial deenergization and release of proapoptotic proteins after pathological stress, e.g. ischemia/reperfusion. Brain mitochondria ex- hibit unique PTP characteristics, including relative re- sistance to inhibition by cyclosporin A. In this study, we report that 2-aminoethoxydiphenyl borate blocks Ca 2 � - induced Ca 2 � release in isolated, non-synaptosomal rat brain mitochondria in the presence of physiological con- centrations of ATP and Mg 2 � .Ca 2 � release was not me - diated by the mitochondrial Na � /Ca 2 � exchanger or by reversal of the uniporter responsible for energy-depend- ent Ca 2 � uptake. Loss of mitochondrial Ca 2 � was accom - panied by release of cytochrome c and pyridine nucleo- tides, indicating an increase in permeability of both the inner and outer mitochondrial membranes. Under these conditions, Ca 2 � -induced opening of the PTP was not blocked by cyclosporin A, antioxidants, or inhibitors of phospholipase A 2 or nitric-oxide synthase but was abol - ished by pretreatment with bongkrekic acid. These find- ings indicate that in the presence of adenine nucleotides and Mg 2 � ,Ca 2 � -induced PTP in non-synaptosomal brain mitochondria exhibits a unique pattern of sensitivity to inhibitors and is particularly responsive to 2-amino- ethoxydiphenyl borate.

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