Impaired insulin secretion and beta-cell loss in tissue-specific knockout mice with mitochondrial diabetes.
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.
Silva
J P
JP
Department of Molecular Medicine, Karolinska Institutet, Karolinska Hospital, Stockholm, Sweden.
Köhler
M
M
Graff
C
C
Oldfors
A
A
Magnuson
M A
MA
Berggren
P O
PO
Larsson
N G
NG
D000255:Adenosine Triphosphate / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000032:analysis*; D004268:DNA-Binding Proteins; D003920:Diabetes Mellitus / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D003576:Electron Transport Complex IV / Q000032:analysis; D005089:Exocytosis; D018390:Gene Targeting; D005947:Glucose / Q000494:pharmacology; D006609:High Mobility Group Proteins; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D019426:Integrases / Q000378:metabolism; D017136:Ion Transport; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; D009928:Organ Specificity; D010085:Oxidative Phosphorylation; D015221:Potassium Channels / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012636:Secretory Rate; D013385:Succinate Dehydrogenase / Q000032:analysis; D015534:Trans-Activators; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic; D019076:Transgenes; D014764:Viral Proteins; D029867:Xenopus Proteins
D020746:Calcium Channels, L-Type; D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D007328:Insulin; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; D015221:Potassium Channels; D011993:Recombinant Fusion Proteins; C499631:TFAM protein, human; C081930:Tfam protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D014764:Viral Proteins; C097078:XL-MTTFA protein, Xenopus; D029867:Xenopus Proteins; C422562:mitochondrial transcription factor A; D000255:Adenosine Triphosphate; D013385:Succinate Dehydrogenase; D003576:Electron Transport Complex IV; C045073:Cre recombinase; D019426:Integrases; D005947:Glucose; D002118:Calcium