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

被引：19

作者：

Gainutdinov, T. ^{[1
,2
]}

Molkentin, J. D. ^{[3
]}

Siemen, D. ^{[1
]}

Ziemer, M. ^{[1
]}

Debska-Vielhaber, G. ^{[1
]}

Vielhaber, S. ^{[1
]}

Gizatullina, Z. ^{[4
]}

Orynbayeva, Z. ^{[5
]}

Gellerich, F. N. ^{[1
,4
]}

机构：

[1] Univ Magdeburg, Dept Neurol, D-39120 Magdeburg, Germany

[2] Acad Sci Tatarstan, Inst Ecol & Use Mineral Resources, Kazan 420087, Russia

[3] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Howard Hughes Med Inst, Dept Pediat, Cincinnati, OH 45229 USA

[4] Leibniz Inst Neurobiol, D-39118 Magdeburg, Germany

[5] Drexel Univ, Coll Med, Dept Surg, Philadelphia, PA 19102 USA

来源：

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS | 2015年 / 579卷

关键词：

Cyclophilin D; Cyclosporin A; Brain mitochondria; Glutamate; Complex I respiration; Mitochondrial permeability transition; Ca2+ stress; PERMEABILITY TRANSITION PORE; CYCLOSPORINE-A CAUSES; CELL-DEATH; INNER MEMBRANE; RESPIRATORY-CHAIN; OXIDATIVE STRESS; CALCIUM; INHIBITION; COMPLEX; BINDING;

D O I：

10.1016/j.abb.2015.05.009

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 Ca2+ 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 Ca2+ effects than BMWT. Under the elevated Ca2+ and correspondingly decreased membrane potential the dose response in BMKO shifts to higher Ca2+ concentrations as compared to BMWT. However, significantly high Ca2+ 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 Ca2+. Due to missing of CypD the BMKO can favor PT only at high Ca2+ 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 Ca2+ stress. (C) 2015 Published by Elsevier Inc.

引用

页码：40 / 46

页数：7

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