Gainutdinov 2015 Arch Biochem Biophys

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Gainutdinov T, Molkentin JD, Siemen D, Ziemer M, Debska-Vielhaber G, Vielhaber S, Gizatullina Z, Orynbayeva Z, Gellerich FN (2015) Knockout of cyclophilin D in Ppif(-/-) mice increases stability of brain mitochondria against Ca(2+) stress. Arch Biochem Biophys 579:40-6.

» PMID: 26032335

Gainutdinov T, Molkentin JD, Siemen D, Ziemer M, Debska-Vielhaber G, Vielhaber S, Gizatullina Z, Orynbayeva Zulfiya, Gellerich FN (2015) Arch Biochem Biophys

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 (BMWT) and CypD knockout (Ppif(-/-)) mice (BMKO) with and without CypD inhibitor Cyclosporin A (CsA) under normal and Ca(2+) stress conditions. Our data demonstrate that BMKO are characterized by higher rates of glutamate/malate-dependent oxidative phosphorylation, higher membrane potential and higher resistance to detrimental Ca(2+) effects than BMWT. Under the elevated Ca(2+) and correspondingly decreased membrane potential the dose response in BMKO shifts to higher Ca(2+) concentrations as compared to BMWT. However, significantly high Ca(2+) levels result in complete loss of membrane potential in BMKO, too. CsA diminishes the loss of membrane potential in BMWT but has no protecting effect in BMKO. 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 BMKO 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.

Keywords: Brain mitochondria, Ca(2+) stress, Complex I respiration, Cyclophilin D, Cyclosporin A, Glutamate, Mitochondrial permeability transition, Safranin, Calcium Green-5 N

O2k-Network Lab: DE Magdeburg Klinik Neurologie, DE Magdeburg Siemen D, DE Magdeburg Gellerich FN, US PA Philadelphia Orynbayeva Z


Labels: MiParea: Respiration, mt-Membrane, Genetic knockout;overexpression, Pharmacology;toxicology 

Stress:Permeability transition  Organism: Mouse  Tissue;cell: Nervous system  Preparation: Isolated mitochondria 

Regulation: Calcium  Coupling state: LEAK, OXPHOS  Pathway: N, S, ROX  HRR: Oxygraph-2k