Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10883159 | Mitochondrion | 2011 | 9 Pages |
Abstract
We studied the functional properties of isolated brain mitochondria (BM) prepared from total rat brain (BMtotal) or from cerebral subregions under basal and Ca2+ overload conditions in order to evaluate the effects of cyclosporine A (CsA) in a regiospecific manner. CsA-induced effects were compared with those of two derivatives-the none-immunosuppressive [O-(NH2(CH2)5NHC(O)CH2)-D-Ser]8-CsA (Cs9) and its congener, the immunosuppressive [D-Ser]8-CsA. The glutamate/malate-dependent state 3 respiration of mitochondria (state 3glu/mal) differed in region-specific manner (cortex > striatum = cerebellum > substantia nigra > hippocampus), but was significantly increased by 1 μM CsA (+ 21 ± 5%) in all regions. Ca2+ overload induced by addition of 20 μM Ca2+ caused a significant decrease of state 3glu/mal (â45 to â55%) which was almost completely prevented in the presence of 1 μM CsA, 1 μM Cs9 or 1 μM [D-Ser]8-CsA. Mitochondrial Ca2+ accumulation thresholds linked to permeability transition (PT) as well as the rate and completeness of mitochondrial Ca2+ accumulation differed between different brain regions. For the first time, we provide a detailed, regiospecific analysis of Ca2+-dependent properties of brain mitochondria. Regardless of their immunosuppressive impact, CsA and its analogues improved mitochondrial functional properties under control conditions. They also preserved brain mitochondria against Ca2+ overload-mediated PT and functional impairments. Since Cs9 does not mediate immunosuppression, it might be used as a more specific PT inhibitor than CsA.
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Authors
Zemfira Z. Gizatullina, Timur M. Gaynutdinov, Hanno Svoboda, Doreen Jerzembek, Annette Knabe, Stefan Vielhaber, Miroslav Malesevic, Hans-Jochen Heinze, Gunter Fischer, Frank Striggow, Frank N. Gellerich,