Impaired insulin secretion and beta-cell loss in tissue-specific knockout mice with mitochondrial diabetes

Nat Genet. 2000 Nov;26(3):336-40. doi: 10.1038/81649.

Abstract

Mitochondrial dysfunction is an important contributor to human pathology and it is estimated that mutations of mitochondrial DNA (mtDNA) cause approximately 0.5-1% of all types of diabetes mellitus. We have generated a mouse model for mitochondrial diabetes by tissue-specific disruption of the nuclear gene encoding mitochondrial transcription factor A (Tfam, previously mtTFA; ref. 7) in pancreatic beta-cells. This transcriptional activator is imported to mitochondria, where it is essential for mtDNA expression and maintenance. The Tfam-mutant mice developed diabetes from the age of approximately 5 weeks and displayed severe mtDNA depletion, deficient oxidative phosphorylation and abnormal appearing mitochondria in islets at the ages of 7-9 weeks. We performed physiological studies of beta-cell stimulus-secretion coupling in islets isolated from 7-9-week-old mutant mice and found reduced hyperpolarization of the mitochondrial membrane potential, impaired Ca(2+)-signalling and lowered insulin release in response to glucose stimulation. We observed reduced beta-cell mass in older mutants. Our findings identify two phases in the pathogenesis of mitochondrial diabetes; mutant beta-cells initially display reduced stimulus-secretion coupling, later followed by beta-cell loss. This animal model reproduces the beta-cell pathology of human mitochondrial diabetes and provides genetic evidence for a critical role of the respiratory chain in insulin secretion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Age Factors
  • Animals
  • Calcium / pharmacology
  • Calcium Channels, L-Type / metabolism
  • DNA, Mitochondrial / analysis*
  • DNA-Binding Proteins*
  • Diabetes Mellitus / genetics*
  • Diabetes Mellitus / pathology
  • Disease Models, Animal*
  • Disease Progression
  • Electron Transport Complex IV / analysis
  • Exocytosis
  • Gene Targeting
  • Glucose / pharmacology
  • High Mobility Group Proteins*
  • Humans
  • Insulin / metabolism*
  • Insulin Secretion
  • Integrases / metabolism
  • Ion Transport
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology*
  • Mice
  • Mice, Transgenic
  • Mitochondrial Proteins*
  • Nuclear Proteins*
  • Organ Specificity
  • Oxidative Phosphorylation
  • Potassium Channels / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Secretory Rate
  • Succinate Dehydrogenase / analysis
  • Trans-Activators*
  • Transcription Factors / deficiency*
  • Transcription Factors / genetics
  • Transcription Factors / physiology
  • Transcription, Genetic
  • Transgenes
  • Viral Proteins*
  • Xenopus Proteins*

Substances

  • Calcium Channels, L-Type
  • DNA, Mitochondrial
  • DNA-Binding Proteins
  • High Mobility Group Proteins
  • Insulin
  • Mitochondrial Proteins
  • Nuclear Proteins
  • Potassium Channels
  • Recombinant Fusion Proteins
  • TFAM protein, human
  • Tfam protein, mouse
  • Trans-Activators
  • Transcription Factors
  • Viral Proteins
  • XL-MTTFA protein, Xenopus
  • Xenopus Proteins
  • mitochondrial transcription factor A
  • Adenosine Triphosphate
  • Succinate Dehydrogenase
  • Electron Transport Complex IV
  • Cre recombinase
  • Integrases
  • Glucose
  • Calcium