Mitochondrial diabetes in mice expressing a dominant-negative allele of nuclear respiratory factor-1 (NRF-1) in pancreatic and β-cells

Abstract

Genetic polymorphisms in nuclear respiratory factor-1 (NRF1), a key transcriptional regulator of nuclear-encoded mitochondrial proteins, have been linked to diabetes. Homozygous deletion of Nrf1 is embryonic lethal in mice. Our goal was to generate mice with {beta}-cell-specific reduction in NRF1 function to investigate the relationship between NRF1 and diabetes. We report the generation of mice expressing a dominant-negative allele of Nrf1 (DNNRF1) in pancreatic {beta}-cells. Heterozygous transgenic mice had high fed blood glucose levels detected at 3 wks of age, which persisted through adulthood. Plasma insulin levels in DNNRF1 transgenic mice were reduced, while insulin sensitivity remained intact in young animals. Islet size was reduced with increased numbers of apoptotic cells, and insulin content in islets by immunohistochemistry was low. Glucose-stimulated insulin secretion in isolated islets was reduced in DNNRF1-mice, but partially rescued by KCl, suggesting that decreased mitochondrial function contributed to the insulin secretory defect. Electron micrographs demonstrated abnormal mitochondrial morphology in {beta}- cells. Expression of NRF1 target genes Tfam, T@1m and T@2m, and islet cytochrome c oxidase and succinate dehydrogenase activities were reduced in DNNRF1-mice. Rescue of mitochondrial function with low level activation of transgenic c-Myc in {beta}-cells was sufficient to restore {beta}-cell mass and prevent diabetes. This study demonstrates that reduced NRF1 function can lead to loss of {beta}-cell function and establishes a model to study the interplay between regulators of bi- genomic gene transcription in diabetes.