Knockout of cyclophilin D in Ppif−/− mice increases stability of brain mitochondria against Ca2+ stress

Abstract The mitochondrial peptidyl prolyl isomerase cyclophilin D (CypD) activates permeability transition (PT). To study the role of CypD in this process we compared the functions of brain mitochondria isolated from wild type (BM WT ) and CypD knockout ( Ppif −/− ) mice (BM KO ) with and without CypD inhibitor Cyclosporin A (CsA) under normal and Ca 2+ stress conditions. Our data demonstrate that BM KO are characterized by higher rates of glutamate/malate-dependent oxidative phosphorylation, higher membrane potential and higher resistance to detrimental Ca 2+ effects than BM WT . Under the elevated Ca 2+ and correspondingly decreased membrane potential the dose response in BM KO shifts to higher Ca 2+ concentrations as compared to BM WT . However, significantly high Ca 2+ levels result in complete loss of membrane potential in BM KO , too. CsA diminishes the loss of membrane potential in BM WT but has no protecting effect in BM KO . The results are in line with the assumption that PT is regulated by CypD under the control of matrix Ca 2+ . Due to missing of CypD the BM KO can favor PT only at high Ca 2+ concentrations. It is concluded that CypD sensitizes the brain mitochondria to PT, and its inhibition by CsA or CypD absence improves the complex I-related mitochondrial function and increases mitochondria stability against Ca 2+ stress.