Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU Grossman School of Medicine, New York, New York, 10016, USA.
Department of Chemistry, University of Albany, State University of New York, Albany, NY, 12222, USA.
Nat Commun. 2023 Oct 30;14(1):6900. doi: 10.1038/s41467-023-42521-x.
Inter-organelle contact and communication between mitochondria and sarco/endoplasmic reticulum (SR/ER) maintain cellular homeostasis and are profoundly disturbed during tissue ischemia. We tested the hypothesis that the formin Diaphanous-1 (DIAPH1), which regulates actin dynamics, signal transduction and metabolic functions, contributes to these processes. We demonstrate that DIAPH1 interacts directly with Mitofusin-2 (MFN2) to shorten mitochondria-SR/ER distance, thereby enhancing mitochondria-ER contact in cells including cardiomyocytes, endothelial cells and macrophages. Solution structure studies affirm the interaction between the Diaphanous Inhibitory Domain and the cytosolic GTPase domain of MFN2. In male rodent and human cardiomyocytes, DIAPH1-MFN2 interaction regulates mitochondrial turnover, mitophagy, and oxidative stress. Introduction of synthetic linker construct, which shorten the mitochondria-SR/ER distance, mitigated the molecular and functional benefits of DIAPH1 silencing in ischemia. This work establishes fundamental roles for DIAPH1-MFN2 interaction in the regulation of mitochondria-SR/ER contact networks. We propose that targeting pathways that regulate DIAPH1-MFN2 interactions may facilitate recovery from tissue ischemia.
细胞器间的联系和线粒体与肌浆/内质网（SR/ER）之间的通讯维持着细胞的内稳态，在组织缺血时会受到严重干扰。我们检验了这样一个假设，即调节肌动蛋白动力学、信号转导和代谢功能的formin Diaphanous-1（DIAPH1）有助于这些过程。我们证明 DIAPH1 与线粒体外膜融合蛋白 2（MFN2）直接相互作用，缩短线粒体-SR/ER 距离，从而增强包括心肌细胞、内皮细胞和巨噬细胞在内的细胞中线粒体-ER 接触。溶液结构研究证实了 Diaphanous Inhibitory Domain 和 MFN2 胞质 GTPase 结构域之间的相互作用。在雄性啮齿动物和人类心肌细胞中，DIAPH1-MFN2 相互作用调节线粒体周转、线粒体自噬和氧化应激。引入缩短线粒体-SR/ER 距离的合成连接子构建体，减轻了 DIAPH1 沉默在缺血中的分子和功能益处。这项工作确立了 DIAPH1-MFN2 相互作用在调节线粒体-SR/ER 接触网络中的基本作用。我们提出，靶向调节 DIAPH1-MFN2 相互作用的途径可能有助于从组织缺血中恢复。
