Department of Biological Sciences, Purdue University West Lafayette, West Lafayette, United States.
Cell and Molecular Physiology, Loyola University Chicago, Chicago, United States.
Elife. 2023 Sep 19;12:e88828. doi: 10.7554/eLife.88828.
Cell spreading and migration play central roles in many physiological and pathophysiological processes. We have previously shown that MFN2 regulates the migration of human neutrophil-like cells via suppressing Rac activation. Here, we show that in mouse embryonic fibroblasts, MFN2 suppresses RhoA activation and supports cell polarization. After initial spreading, the wild-type cells polarize and migrate, whereas the cells maintain a circular shape. Increased cytosolic Ca resulting from the loss of Mfn2 is directly responsible for this phenotype, which can be rescued by expressing an artificial tether to bring mitochondria and endoplasmic reticulum to close vicinity. Elevated cytosolic Ca activates Ca/calmodulin-dependent protein kinase II, RhoA, and myosin light-chain kinase, causing an overactivation of nonmuscle myosin II, leading to a formation of a prominent F-actin ring at the cell periphery and increased cell contractility. The peripheral actin band alters cell physics and is dependent on substrate rigidity. Our results provide a novel molecular basis to understand how MFN2 regulates distinct signaling pathways in different cells and tissue environments, which is instrumental in understanding and treating MFN2-related diseases.
细胞的扩展和迁移在许多生理和病理生理过程中起着核心作用。我们之前已经表明，MFN2 通过抑制 Rac 的激活来调节人中性粒细胞样细胞的迁移。在这里，我们表明在鼠胚胎成纤维细胞中，MFN2 抑制 RhoA 的激活并支持细胞极化。在初始扩展后，野生型细胞发生极化并迁移，而 细胞保持圆形。由于 Mfn2 的缺失导致细胞内钙离子浓度升高，这是导致这种表型的直接原因，通过表达一种人工连接蛋白将线粒体和内质网拉近可以挽救这种表型。升高的细胞溶质 Ca 激活钙/钙调蛋白依赖性蛋白激酶 II、RhoA 和肌球蛋白轻链激酶，导致非肌球蛋白 II 的过度激活，导致细胞外周形成明显的 F-肌动蛋白环和增加细胞收缩力。外周肌动蛋白带改变了细胞的物理性质，并依赖于底物的刚性。我们的研究结果为理解 MFN2 如何在不同的细胞和组织环境中调节不同的信号通路提供了新的分子基础，这对于理解和治疗与 MFN2 相关的疾病至关重要。
