Division of Metabolism, Endocrinology & Diabetes and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48105, United States.
Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15260, United States.
Nat Commun. 2022 Apr 29;13(1):2340. doi: 10.1038/s41467-022-29945-7.
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.
动力蛋白样 GTP 酶 Mitofusin 1 和 2（Mfn1 和 Mfn2）对于线粒体功能至关重要，这主要归因于它们对分裂/融合动力学的调节。在这里，我们报告说 Mfn1 和 Mfn2 对于葡萄糖刺激的胰岛素分泌（GSIS）至关重要，主要是通过控制线粒体 DNA（mtDNA）含量。虽然 Mfn1 和 Mfn2 单独对于葡萄糖稳态是可有可无的，但β细胞中 Mfn1/2 的联合缺失会降低 mtDNA 含量，损害线粒体形态和网络，并降低呼吸功能，最终导致严重的葡萄糖不耐受。重要的是，基因剂量研究出人意料地揭示了 Mfn1/2 对葡萄糖稳态的控制依赖于 mtDNA 含量的维持，而不是线粒体结构。Mfn1/2 通过调节关键的线粒体转录因子 Tfam 的表达来维持 mtDNA 含量，因为 Tfam 的过表达改善了 Mfn1/2 缺陷β细胞中 mtDNA 含量和 GSIS 的减少。因此，Mfn1 和 Mfn2 在β细胞中的主要生理作用与 mtDNA 含量的维持有关，而不是与线粒体结构有关，Mfn1 和 Mfn2 可能是克服线粒体功能障碍和恢复糖尿病患者葡萄糖控制的有前途的靶点。
