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
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / metabolism
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Age Factors
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Animals
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Calcium / pharmacology
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Calcium Channels, L-Type / metabolism
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DNA, Mitochondrial / analysis*
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DNA-Binding Proteins*
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Diabetes Mellitus / genetics*
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Diabetes Mellitus / pathology
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Disease Models, Animal*
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Disease Progression
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Electron Transport Complex IV / analysis
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Exocytosis
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Gene Targeting
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Glucose / pharmacology
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High Mobility Group Proteins*
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Humans
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Insulin / metabolism*
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Insulin Secretion
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Integrases / metabolism
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Ion Transport
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Islets of Langerhans / metabolism
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Islets of Langerhans / pathology*
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Mice
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Mice, Transgenic
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Mitochondrial Proteins*
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Nuclear Proteins*
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Organ Specificity
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Oxidative Phosphorylation
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Potassium Channels / metabolism
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Recombinant Fusion Proteins / metabolism
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Secretory Rate
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Succinate Dehydrogenase / analysis
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Trans-Activators*
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Transcription Factors / deficiency*
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Transcription Factors / genetics
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Transcription Factors / physiology
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Transcription, Genetic
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Transgenes
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Viral Proteins*
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Xenopus Proteins*
Substances
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Calcium Channels, L-Type
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DNA, Mitochondrial
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DNA-Binding Proteins
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High Mobility Group Proteins
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Insulin
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Mitochondrial Proteins
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Nuclear Proteins
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Potassium Channels
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Recombinant Fusion Proteins
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TFAM protein, human
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Tfam protein, mouse
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Trans-Activators
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Transcription Factors
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Viral Proteins
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XL-MTTFA protein, Xenopus
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Xenopus Proteins
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mitochondrial transcription factor A
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Adenosine Triphosphate
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Succinate Dehydrogenase
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Electron Transport Complex IV
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Cre recombinase
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Integrases
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Glucose
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Calcium