Journal article
Vaibhav Sidarala, Jie Zhu, Elena Levi-D'Ancona, Gemma L. Pearson, Emma C. Reck, E. Walker, B. Kaufman, S. Soleimanpour
Nature Communications, 2022
Nature Communications, 2022
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APA
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Sidarala, V., Zhu, J., Levi-D'Ancona, E., Pearson, G. L., Reck, E. C., Walker, E., … Soleimanpour, S. (2022). Mitofusin 1 and 2 regulation of mitochondrial DNA content is a critical determinant of glucose homeostasis. Nature Communications.
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Sidarala, Vaibhav, Jie Zhu, Elena Levi-D'Ancona, Gemma L. Pearson, Emma C. Reck, E. Walker, B. Kaufman, and S. Soleimanpour. “Mitofusin 1 and 2 Regulation of Mitochondrial DNA Content Is a Critical Determinant of Glucose Homeostasis.” Nature Communications (2022).
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Sidarala, Vaibhav, et al. “Mitofusin 1 and 2 Regulation of Mitochondrial DNA Content Is a Critical Determinant of Glucose Homeostasis.” Nature Communications, 2022.
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@article{vaibhav2022a,
title = {Mitofusin 1 and 2 regulation of mitochondrial DNA content is a critical determinant of glucose homeostasis},
year = {2022},
journal = {Nature Communications},
author = {Sidarala, Vaibhav and Zhu, Jie and Levi-D'Ancona, Elena and Pearson, Gemma L. and Reck, Emma C. and Walker, E. and Kaufman, B. and Soleimanpour, S.}
}
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. Sidarala et al. examine the importance of the mitochondrial structural proteins, Mitofusins 1 and 2 (Mfn1/2), in diabetes. They find that Mfn1/2 control blood glucose by preserving mitochondrial DNA content, rather than mitochondrial structure.