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Free keywords:
Adenosine Triphosphate/metabolism
Age Factors
Animals
Calcium/pharmacology
Calcium Channels, L-Type/metabolism
DNA, Mitochondrial/*analysis
*DNA-Binding Proteins
Diabetes Mellitus/*genetics/pathology
*Disease Models, Animal
Disease Progression
Electron Transport Complex IV/analysis
Exocytosis
Gene Targeting
Glucose/pharmacology
*High Mobility Group Proteins
Humans
Insulin/*secretion
Integrases/metabolism
Ion Transport
Islets of Langerhans/metabolism/*pathology/secretion
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/genetics/physiology
Transcription, Genetic
Transgenes
*Viral Proteins
*Xenopus Proteins
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.
