Mitochondrial dynamics and metabolic regulation

Mitochondria are dynamic organelles that frequently undergo fusion and fission. Mitochondrial dynamics has been shown to be essential for a variety of cellular functions. We have previously shown that exposure of beta cells to high levels of glucose and free fatty acids, an in vitro model of diabetes, leads to a decrease in mitochondrial fusion capacity.We find that diet induced obesity was accompanied by decreased levels of mitofusin 2 (Mfn2), an outer mitochondrial membrane fusion protein, in islets of C57BL/6 mice. To assess the functional significance of this finding in vivo, we generated a beta cell specific knockout of Mfn2 (βMfn2KO). Examination of mitochondrial structures in βMfn2KO beta cells reveals that Mfn2 deficiency by itself is sufficient to cause fragmentation of the mitochondrial network and an increase in heterogeneity of mitochondrial membrane potential. βMfn2KO mice display hyperglycemia and striking obesity compared to littermate controls. Islets isolated from βMfn2KO mice display a 2.5 fold increase in basal insulin secretion with no change in glucose stimulated insulin secretion in response to 15mM glucose compared to control islets. Lack of beta cell Mfn2 represents a scenario where initial beta cell mitochondrial dysfunction leads to whole body metabolic dysfunction, identifying beta cells as having an essential role in the development of obesity and type 2 diabetes.