Mitofusin 1 and 2 regulation of mitochondrial DNA content is a critical determinant of glucose homeostasis

Vaibhav Sidarala, Jie Zhu, Elena Levi-D’Ancona, Gemma L. Pearson, Emma C. Reck, Emily M. Walker, Brett A. Kaufman and Scott A. Soleimanpour ()
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Vaibhav Sidarala: University of Michigan
Jie Zhu: University of Michigan
Elena Levi-D’Ancona: University of Michigan
Gemma L. Pearson: University of Michigan
Emma C. Reck: University of Michigan
Emily M. Walker: University of Michigan
Brett A. Kaufman: University of Pittsburgh School of Medicine
Scott A. Soleimanpour: University of Michigan

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract The dynamin-like GTPases Mitofusin 1 and 2 (Mfn1 and Mfn2) are essential for mitochondrial function, which has been principally attributed to their regulation of fission/fusion dynamics. Here, we report that Mfn1 and 2 are critical for glucose-stimulated insulin secretion (GSIS) primarily through control of mitochondrial DNA (mtDNA) content. Whereas Mfn1 and Mfn2 individually were dispensable for glucose homeostasis, combined Mfn1/2 deletion in β-cells reduced mtDNA content, impaired mitochondrial morphology and networking, and decreased respiratory function, ultimately resulting in severe glucose intolerance. Importantly, gene dosage studies unexpectedly revealed that Mfn1/2 control of glucose homeostasis was 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 β-cells. Thus, the primary physiologic role of Mfn1 and 2 in β-cells is coupled to the preservation of mtDNA content rather than mitochondrial architecture, and Mfn1 and 2 may be promising targets to overcome mitochondrial dysfunction and restore glucose control in diabetes.

Date: 2022
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DOI: 10.1038/s41467-022-29945-7

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