Properties of the permeability transition pore in mitochondria devoid of cyclophilin D
Properties of the permeability transition pore in mitochondria devoid of cyclophilin D
复制标题
DOI：
10.1074/jbc.c500089200
复制
发表时间：
2005-05-13
影响因子：
4.8
通讯作者：
Bernardi, P
中科院分区：
文献类型：
--
作者：
Basso, E;Fante, L;Bernardi, P
我们研究了线粒体亲环素D(CYP-D)编码基因Ppif失活小鼠肝脏线粒体通透性转换孔(PTP)的性质。来自Ppif(-/-)小鼠的线粒体没有CYP-D，并且显示出PTP对Ca~(2+)的显著减敏，因为在与菌株匹配的野生型线粒体中，打开孔所需的Ca~(2+)负荷大约是打开孔所需的两倍。缺乏CYP-D的线粒体对环孢菌素A(CsA)不敏感，CsA只增加野生型小鼠线粒体的钙保留能力。野生型和Ppif(-/-)小鼠线粒体对泛醌0、去极化、pH、腺嘌呤核苷酸和硫醇氧化剂的PTP反应相似。这些实验表明：(I)在没有CYP-D的情况下，PTP可以形成和开放；(Ii)CYP-D是CsA抑制PTP的靶标；(Iii)CYP-D调节PTP对钙的敏感性，但不受质子电化学梯度、腺嘌呤核苷酸和氧化应激的调节。这些结果对我们目前对PTP及其在体外和体内的调控有重要的意义。
We have studied the properties of the permeability transition pore (PTP) in mitochondria from the liver of mice where the Ppif gene encoding for mitochondrial Cyclophilin D (CyP-D) had been inactivated. Mitochondria from Ppif(-/-) mice had no CyP-D and displayed a striking desensitization of the PTP to Ca2+, in that pore opening required about twice the Ca2+ load necessary to open the pore in strain-matched, wild-type mitochondria. Mitochondria lacking CyP-D were insensitive to Cyclosporin A (CsA), which increased the Ca2+ retention capacity only in mitochondria from wild-type mice. The PTP response to ubiquinone 0, depolarization, pH, adenine nucleotides, and thiol oxidants was similar in mitochondria from wild-type and Ppif(-/-) mice. These experiments demonstrate that (i) the PTP can form and open in the absence of CyP-D, (ii) that CyP-D represents the target for PTP inhibition by CsA, and (iii) that CyP-D modulates the sensitivity of the PTP to Ca2+ but not its regulation by the proton electrochemical gradient, adenine nucleotides, and oxidative stress. These results have major implications for our current understanding of the PTP and its modulation in vitro and in vivo.