Mitochondrial health and function are critical for coupling glucose metabolism to insulin secretion in pancreatic β-cells. Mitochondria are highly dynamic organelles, and mitochondrial fusion is essential for regulating mitochondrial architecture. To decipher the role of mitochondrial fusion in β-cell function, we investigated the roles of dynamin-like GTPases mitofusins 1 and 2 (Mfn1 and Mfn2) in the maintenance of functional mitochondria. We observe that while loss of Mfn1 or Mfn2 is dispensable for β-cell function, combined loss of both Mfn1 and Mfn2 (Mfn1/2) in β-cells results in impaired glucose tolerance and glucose-stimulated insulin secretion (GSIS). Our assessments indicate decreased respiratory capacity in Mfn1/2-deficient β-cells, coupled with increased mitochondrial fragmentation, loss of mtDNA content, and decreased expression of subunits comprising the electron transport chain. Gene dosage studies suggest that a single allele of Mfn2 is sufficient to maintain mtDNA content and glucose homeostasis, independent of maintenance of mitochondrial structure and reticular network. Further investigations revealed that Mfn1/2-deficiency reduced mtDNA copy number through decreased levels of Tfam, a critical regulator of mitochondrial nucleoid packaging and maintenance. Overexpression of Tfam rescued mtDNA levels and GSIS in Mfn1/2 deficient β-cells. Lastly, Mfn1/2 agonists restored mtDNA levels and β-cell function in db/db mouse islets, a model for type 2 diabetes. Together, our studies demonstrate concerted roles of Mfn1 and 2 in the maintenance of mitochondrial structure and mtDNA in β-cells, and therefore propose novel therapeutic targets to restore glucose homeostasis in diabetes.
V. Sidarala: None. J. Zhu: None. G. Pearson: None. S. Soleimanpour: None.