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bioRxiv · 10.1101/2021.01.10.426151

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

Sidarala, V.·Zhu, J.·Pearson, G. L.·Reck, E. C.·Kaufman, B. A.·Soleimanpour, S. A.
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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 {beta}-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 {beta}-cells. Thus, the primary physiologic role of Mfn1 and 2 in {beta}-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.

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Sidarala, V., Zhu, J., Pearson, G. L., Reck, E. C., Kaufman, B. A., Soleimanpour, S. A.. 2021-01-11. Mitofusins 1 and 2 collaborate to fuel pancreatic beta cell insulin release via regulation of both mitochondrial structure and DNA content. https://doi.org/10.1101/2021.01.10.426151

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