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Abstract：
Mechanical cues from the tissue microenvironment, such as the stiffness of the extracellular matrix, modulate cellular forms and functions. As numerous studies have shown, this modulation depends on the stiffness-dependent remodeling of cytoskeletal elements. In contrast, very little is known about how the intracellular organelles such as mitochondria respond to matrix stiffness and whether their form, function, and localization change accordingly. Here, we performed an extensive quantitative characterization of mitochondrial morphology, subcellular localization, dynamics, and membrane tension on soft and stiff matrices. This characterization revealed that while matrix stiffness affected all these aspects, matrix stiffening most distinctively led to an increased perinuclear clustering of mitochondria. Subsequently, we could identify the matrix stiffness-sensitive perinuclear localization of filamin as the key factor dictating this perinuclear clustering. The perinuclear and peripheral mitochondrial populations differed in their motility on soft matrix but surprisingly they did not show any difference on stiff matrix. Finally, perinuclear mitochondrial clustering appeared to be crucial for the nuclear localization of RUNX2 and hence for priming human mesenchymal stem cells towards osteogenesis on a stiff matrix. Taken together, we elucidate a dependence of mitochondrial localization on matrix stiffness, which possibly enables a cell to adapt to its microenvironment.
摘要：
来自组织微环境的机械线索，例如细胞外基质的硬度，调节细胞形式和功能。正如许多研究表明的那样，这种调节取决于细胞骨架元件的刚度依赖性重塑。相比之下,关于细胞内细胞器如线粒体如何响应基质硬度以及它们的形式,函数,和本地化相应的变化。这里,我们对线粒体形态进行了广泛的定量表征，亚细胞定位，动力学,和软和硬基质上的膜张力。这一表征表明，虽然基体刚度影响所有这些方面，基质硬化最明显地导致线粒体核周聚集增加。随后，我们可以确定丝素的矩阵刚度敏感核周定位是决定这种核周聚类的关键因素。核周和外周线粒体种群在软基质上的运动性不同，但令人惊讶的是，它们在硬基质上没有任何差异。最后,核周线粒体聚集似乎对于RUNX2的核定位至关重要，因此对于促使人间充质干细胞在坚硬的基质上成骨至关重要。一起来看,我们阐明了线粒体定位对基质硬度的依赖性，这可能使细胞适应其微环境。[媒体:见文本][媒体:见文本][媒体:见文本][媒体:见文本]。
