Mitofusins 1 and 2 collaborate to fuel pancreatic beta cell insulin release via regulation of both mitochondrial structure and DNA content

Mitochondria are vital for {beta}-cell function, yet the importance of mitochondrial fusion for glucose homeostasis is uncertain. Here, we report that the dynamin-like GTPases Mitofusin 1 and 2 (Mfn1 and Mfn2) are critical for glucose-stimulated insulin secretion (GSIS). Whereas Mfn1 and Mfn2 individually were dispensable for glucose control, combined Mfn1/2 deletion in {beta}-cells induced mitochondrial fragmentation, reduced mtDNA content, and impaired respiratory function, ultimately resulting in severe glucose intolerance. Importantly, gene dosage studies revealed that Mfn1/2 control of glucose homeostasis is dependent on maintenance of mtDNA content, rather than mitochondrial structure. Mfn1/2 maintain mtDNA content by regulating the expression of the crucial mitochondrial transcription factor Tfam, as Tfam overexpression ameliorated the reduction in mtDNA content and GSIS in Mfn1/2-deficient {beta}-cells. Further, mitofusin agonists rescued mtDNA content and GSIS in islets from db/db mice, a model of type 2 diabetes. Thus, Mfn1 and 2 act collectively to promote both optimal mitochondrial dynamics and mtDNA copy number in {beta}-cells, and may be promising therapeutic targets to improve insulin release in diabetes.