Gauthier Benoit R, Wiederkehr Andreas, Baquié Mathurin, Dai Chunhua, Powers Alvin C, Kerr-Conte Julie, Pattou François, MacDonald Raymond J, Ferrer Jorge, Wollheim Claes B
Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
Cell Metab. 2009 Aug;10(2):110-8. doi: 10.1016/j.cmet.2009.07.002.
Mutations in the transcription factor Pdx1 cause maturity-onset diabetes of the young 4 (MODY4). Islet transduction with dominant-negative Pdx1 (RIPDN79PDX1) impairs mitochondrial metabolism and glucose-stimulated insulin secretion (GSIS). Transcript profiling revealed suppression of nuclear-encoded mitochondrial factor A (TFAM). Herein, we show that Pdx1 suppression in adult mice reduces islet TFAM expression coinciding with hyperglycemia. We define TFAM as a direct target of Pdx1 both in rat INS1 cells and human islets. Adenoviral overexpression of TFAM along with RIPDN79PDX1 in isolated rat islets rescued mitochondrial DNA (mtDNA) copy number and restored respiratory chain activity as well as glucose-induced ATP synthesis and insulin secretion. CGP37157, which blocks the mitochondrial Na(+)/Ca(2+) exchanger, restored ATP generation and GSIS in RIPDN79PDX1 islets, thereby bypassing the transcriptional defect. Thus, the genetic control by the beta cell-specific factor Pdx1 of the ubiquitous gene TFAM maintains beta cell mtDNA vital for ATP production and normal GSIS.
转录因子Pdx1的突变会导致青年发病的成年型糖尿病4（MODY4）。用显性负性Pdx1（RIPDN79PDX1）进行胰岛转导会损害线粒体代谢和葡萄糖刺激的胰岛素分泌（GSIS）。转录谱分析显示核编码的线粒体因子A（TFAM）受到抑制。在此，我们表明成年小鼠中Pdx1的抑制会降低胰岛TFAM的表达，同时伴有高血糖症。我们将TFAM定义为大鼠INS1细胞和人胰岛中Pdx1的直接靶点。在分离的大鼠胰岛中，TFAM与RIPDN79PDX1一起进行腺病毒过表达可挽救线粒体DNA（mtDNA）拷贝数，并恢复呼吸链活性以及葡萄糖诱导的ATP合成和胰岛素分泌。阻断线粒体Na(+)/Ca(2+)交换体的CGP37157可恢复RIPDN79PDX1胰岛中的ATP生成和GSIS，从而绕过转录缺陷。因此，β细胞特异性因子Pdx1对普遍存在的基因TFAM的遗传控制维持了对ATP产生和正常GSIS至关重要的β细胞mtDNA。
