Lee Geum-Hwa, Lee Hwa-Young, Li Bo, Kim Hyung-Ryong, Chae Han-Jung
Department of Pharmacology and Cardiovascular Research Institute, Medical School, Chonbuk National University, Jeonju, 561-181, Republic of Korea.
Department of Dental Pharmacology and Wonkwang Dental Research Institute, School of Dentistry, Wonkwang University, Iksan, 570-749, Republic of Korea.
Sci Rep. 2014 Jun 5;4:5194. doi: 10.1038/srep05194.
A recently studied endoplasmic reticulum (ER) stress regulator, Bax inhibitor-1 (BI-1) plays a regulatory role in mitochondrial Ca(2+) levels. In this study, we identified ER-resident and mitochondria-associated ER membrane (MAM)-resident populations of BI-1. ER stress increased mitochondrial Ca(2+) to a lesser extent in BI-1-overexpressing cells (HT1080/BI-1) than in control cells, most likely as a result of impaired mitochondrial Ca(2+) intake ability and lower basal levels of intra-ER Ca(2+). Moreover, opening of the Ca(2+)-induced mitochondrial permeability transition pore (PTP) and cytochrome c release were regulated by BI-1. In HT1080/BI-1, the basal mitochondrial membrane potential was low and also resistant to Ca(2+) compared with control cells. The activity of the mitochondrial membrane potential-dependent mitochondrial Ca(2+) intake pore, the Ca(2+) uniporter, was reduced in the presence of BI-1. This study also showed that instead of Ca(2+), other cations including K(+) enter the mitochondria of HT1080/BI-1 through mitochondrial Ca(2+)-dependent ion channels, providing a possible mechanism by which mitochondrial Ca(2+) intake is reduced, leading to cell protection. We propose a model in which BI-1-mediated sequential regulation of the mitochondrial Ca(2+) uniporter and Ca(2+)-dependent K(+) channel opening inhibits mitochondrial Ca(2+) intake, thereby inhibiting PTP function and leading to cell protection.
一种最近被研究的内质网（ER）应激调节因子，Bax抑制剂-1（BI-1）在线粒体Ca(2+)水平中发挥调节作用。在本研究中，我们鉴定了BI-1在内质网驻留以及与线粒体相关的内质网膜（MAM）驻留群体。与对照细胞相比，内质网应激在BI-1过表达细胞（HT1080/BI-1）中使线粒体Ca(2+)增加的程度较小，这很可能是由于线粒体Ca(2+)摄取能力受损以及内质网内Ca(2+)基础水平较低所致。此外，Ca(2+)诱导的线粒体通透性转换孔（PTP）的开放和细胞色素c的释放受BI-1调节。在HT1080/BI-1中，基础线粒体膜电位较低，并且与对照细胞相比对Ca(2+)也具有抗性。在存在BI-1的情况下，线粒体膜电位依赖性线粒体Ca(2+)摄取孔即Ca(2+)单向转运体的活性降低。本研究还表明，包括K(+)在内的其他阳离子而非Ca(2+)通过线粒体Ca(2+)依赖性离子通道进入HT1080/BI-1的线粒体，这提供了一种线粒体Ca(2+)摄取减少从而导致细胞保护的可能机制。我们提出了一个模型，其中BI-1介导的对线粒体Ca(2+)单向转运体和Ca(2+)依赖性K(+)通道开放的顺序调节抑制了线粒体Ca(2+)摄取，从而抑制PTP功能并导致细胞保护。
