Tissue-scale architecture and mechanical properties instruct cell behaviour under physiological and diseased conditions, but our understanding of the underlying mechanisms remains fragmentary. Here we show that extracellular matrix stiffness, spatial confinements and applied forces, including stretching of mouse skin, regulate mitochondrial dynamics. Actomyosin tension promotes the phosphorylation of mitochondrial elongation factor 1 (MIEF1), limiting the recruitment of dynamin-related protein 1 (DRP1) at mitochondria, as well as peri-mitochondrial F-actin formation and mitochondrial fission. Strikingly, mitochondrial fission is also a general mechanotransduction mechanism. Indeed, we found that DRP1- and MIEF1/2-dependent fission is required and sufficient to regulate three transcription factors of broad relevance—YAP/TAZ, SREBP1/2 and NRF2—to control cell proliferation, lipogenesis, antioxidant metabolism, chemotherapy resistance and adipocyte differentiation in response to mechanical cues. This extends to the mouse liver, where DRP1 regulates hepatocyte proliferation and identity—hallmark YAP-dependent phenotypes. We propose that mitochondria fulfil a unifying signalling function by which the mechanical tissue microenvironment coordinates complementary cell functions.

组织规模的结构和机械特性指导细胞在生理和疾病条件下的行为，但我们对潜在机制的理解仍然不完整。在这里，我们表明细胞外基质刚度、空间限制和施加的力（包括小鼠皮肤的拉伸）调节线粒体动力学。肌动球蛋白张力促进线粒体延伸因子 1 （MIEF1） 的磷酸化，限制线粒体中动力蛋白相关蛋白 1 （DRP1） 的募集，以及线粒体周围 F-肌动蛋白形成和线粒体裂变。引人注目的是，线粒体裂变也是一种通用的机械转导机制。事实上，我们发现 DRP1 和 MIEF1/2 依赖性裂变是必需的，并且足以调节三种具有广泛相关性的转录因子——YAP/TAZ、SREBP1/2 和 NRF2——以控制细胞增殖、脂肪生成、抗氧化代谢、化疗耐药性和脂肪细胞分化响应机械线索。这延伸到小鼠肝脏，DRP1 调节肝细胞增殖和身份——标志性的 YAP 依赖性表型。我们提出线粒体实现统一的信号传导功能，机械组织微环境通过该功能协调互补的细胞功能。