deletion of the mitochondrial flavoprotein apoptosis inducing factor (aif) induces β-cell apoptosis and impairs β-cell mass删除的线粒体黄素蛋白细胞凋亡诱导因子(aif)细胞凋亡β-cell和损害β-cell质量.pdfVIP

Deletion of the Mitochondrial Flavoprotein Apoptosis Inducing Factor (AIF) Induces b-Cell Apoptosis and Impairs b-Cell Mass 1,2 2 1 2 2 Fabienne T. Schulthess , Sophie Katz , Amin Ardestani , Hiroshi Kawahira , Senta Georgia , Domenico 3 2 1,2 Bosco , Anil Bhushan , Kathrin Maedler * 1 Centre for Biomolecular Interactions, University of Bremen, Bremen, Germany, 2 Larry L. Hillblom Islet Research Center, Department of Medicine, University of California Los Angeles, Los Angeles, California, United States of America, 3 Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of ` Medicine, Geneva, Switzerland Abstract Background: Apoptosis is a hallmark of b-cell death in both type 1 and type 2 diabetes mellitus. Understanding how apoptosis contributes to b-cell turnover may lead to strategies to prevent progression of diabetes. A key mediator of apoptosis, mitochondrial function, and cell survival is apoptosis inducing factor (AIF). In the present study, we investigated the role of AIF on b-cell mass and survival using the Harlequin (Hq) mutant mice, which are hypomorphic for AIF. Methodology/Principal Findings: Immunohistochemical evaluation of pancreata from Hq mutant mice displayed much smaller islets compared to wild-type mice (WT). Analysis of b-cell mass in these mice revealed a greater than 4-fold reduction in b-cell mass together with an 8-fold increase in b-cell apoptosis. Analysis of cell cycle dynamics, using BrdU pulse as a marker for cells in S-phase, did not detect significant differences in