| First Author | Weiss H | Year | 2012 |
| Journal | Endocrinology | Volume | 153 |
| Issue | 10 | Pages | 4666-76 |
| PubMed ID | 22919063 | Mgi Jnum | J:192944 |
| Mgi Id | MGI:5466836 | Doi | 10.1210/en.2012-1296 |
| Citation | Weiss H, et al. (2012) The mitochondrial Atp8 mutation induces mitochondrial ROS generation, secretory dysfunction, and beta-cell mass adaptation in conplastic B6-mtFVB mice. Endocrinology 153(10):4666-76 |
| abstractText | Mutations in mitochondrial DNA (mtDNA) cause a variety of pathologic phenotypes. In this study, we used conplastic mouse strains to characterize the impact of a mtDNA mutation in the Atp8 gene on beta-cell function, reactive oxygen species (ROS) generation, beta-cell mass, and glucose metabolism in response to high-fat diet (HFD). In comparison with B6-mt(AKR) controls, the B6-mt(FVB) strain carries a point mutation of the mtDNA-coded Atp8 gene (ATP synthase), leading to a fragmentated mitochondrial phenotype. Isolated pancreatic islets from 3-month-old B6-mt(FVB) mice showed increased mitochondrial generation of ROS, reduced cellular ATP levels, reduced glucose-induced insulin secretion, higher susceptibility to palmitate stress, and pathological morphology of mitochondria. ROS generation in beta-cells was not affected by changes of the ambient glucose concentrations. Feeding a HFD for 3 months resulted in impaired glucose tolerance in B6-mt(FVB) mice but not in B6-mt(AKR) controls. In B6-mt(FVB) animals, glucose intolerance positively correlated with gain of body weight. Serum insulin levels and beta-cell mass significantly increased in B6-mt(FVB) mice after a 3-month HFD. The data indicate that the mutation in the Atp8 gene induces mitochondrial dysfunction in beta-cells with concomitant impairment of secretory responsiveness. This mitochondrial dysfunction induced a higher susceptibility to metabolic stressors, although this effect appeared not strictly linked to nutrient-induced ROS generation. The Atp8 gene mutation caused mitochondrial dysfunction, apparently stimulating an adaptive increase of beta-cell mass in response to HFD, whereas mitochondrial ROS might have had an supportive role. |
