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Mitofusin 1 and 2 regulation of mitochondrial DNA content is a critical determinant of glucose homeostasis
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Mitofusin 1 and 2 regulation of mitochondrial DNA content is a critical determinant of glucose homeostasis
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Journal Article
Mitofusin 1 and 2 regulation of mitochondrial DNA content is a critical determinant of glucose homeostasis
2022
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 14
/ 14/19
/ 14/28
/ 14/63
/ 38
/ 38/1
/ 38/91
/ 64
/ 64/110
/ Cytology
/ Diabetes
/ DNA
/ DNA, Mitochondrial - genetics
/ DNA, Mitochondrial - metabolism
/ Dynamin
/ Glucose
/ GTP Phosphohydrolases - metabolism
/ Humanities and Social Sciences
/ Insulin
/ Science
