title: Bax inhibitor-1-mediated inhibition of mitochondrial Ca2+ intake regulates mitochondrial permeability transition pore opening and cell death.
abstract: 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.
authors.affiliation: Department of Pharmacology and Cardiovascular Research Institute, Medical School, Chonbuk National University, Jeonju, 561-181, Republic of Korea.
authors.forename: Geum-Hwa
authors.initials: GH
authors.lastname: Lee
authors.affiliation: Department of Pharmacology and Cardiovascular Research Institute, Medical School, Chonbuk National University, Jeonju, 561-181, Republic of Korea.
authors.forename: Hwa-Young
authors.initials: HY
authors.lastname: Lee
authors.affiliation: Department of Pharmacology and Cardiovascular Research Institute, Medical School, Chonbuk National University, Jeonju, 561-181, Republic of Korea.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Dental Pharmacology and Wonkwang Dental Research Institute, School of Dentistry, Wonkwang University, Iksan, 570-749, Republic of Korea.
authors.forename: Hyung-Ryong
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and Cardiovascular Research Institute, Medical School, Chonbuk National University, Jeonju, 561-181, Republic of Korea.
authors.forename: Han-Jung
authors.initials: HJ
authors.lastname: Chae
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D049109:Cell Proliferation; D045304:Cytochromes c / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005354:Fibrosarcoma / Q000378:metabolism* / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000502:physiology*; D000083162:Mitochondrial Permeability Transition Pore; D014407:Tumor Cells, Cultured
chemical_list: D051017:Apoptosis Regulatory Proteins; D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C484209:TMBIM6 protein, human; D045304:Cytochromes c; D002118:Calcium