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

Silva JP, Köhler M, Graff C, Oldfors A, Magnuson MA, Berggren PO, Larsson NG
Nat Genet. 2000 26 (3): 336-40

PMID: 11062475 · DOI:10.1038/81649

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.

MeSH Terms (37)

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

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