Updated project metadata. Tissue-scale architecture and mechanical properties instruct cell behavior in physiological and diseased conditions, but our understanding of the underlying mechanisms remains fragmentary. Here we show that ECM stiffness, spatial confinements, and applied forces including stretching of the mouse skin regulate mitochondrial dynamics. Actomyosin tension promotes phosphorylation of MIEF1, limiting the recruitment of DRP1 at mitochondria, peri-mitochondrial F-actin formation, and mitochondrial fission. Strikingly, mitochondrial fission is also a general mechanotransduction mechanism. Indeed we found that DRP1- and MIEF1-dependent fission is required and sufficient to regulate three transcription factors of broad relevance such as 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 fulfill a unifying signaling function by which the mechanical tissue microenvironment coordinates complementary cell functions.