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

Mitochondrial dysfunction is an important contributor to human pathology(1-4) and it is estimated that mutations of mitochondrial DNA (mtDNA) cause approximately 0.5-1% of all types of diabetes mellitus(5,6). 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(8,9). 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 Ca2+-signalling and lowered insulin release in response to glucose stimulation. We observed reduced beta -cell mass in older mutants. Our findings identity 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.