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

Author

Listed:
  • 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
    University of Michigan
    VA Ann Arbor Healthcare System)

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.

Suggested Citation

  • Vaibhav Sidarala & Jie Zhu & Elena Levi-D’Ancona & Gemma L. Pearson & Emma C. Reck & Emily M. Walker & Brett A. Kaufman & Scott A. Soleimanpour, 2022. "Mitofusin 1 and 2 regulation of mitochondrial DNA content is a critical determinant of glucose homeostasis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29945-7
    DOI: 10.1038/s41467-022-29945-7
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