Mitochondrial fuels ATP in the nucleus to prevent cell cycle arrest during mechanical confinement

Abstract The physical microenvironment regulates cell behaviour during tissue development and disease. Whether mechanical stress and physical space constraints reshape the subcellular localization of organelles and proteins resulting in functional adaptations is, however, unknown. Here, we performed proteomic analysis to understand how proteins reorganise between the nucleus and the cytoplasm when cancer cells are acutely confined. We discovered that cellular confinement induces a strong enrichment of mitochondrial proteins within the nuclear compartment. High-resolution microscopy confirmed that upon confinement mitochondria, in an actin-dependent manner, are trapped within an ER-based net that indents the nucleus. At the functional level, the close proximity of mitochondria and the nucleus results in a nuclear ATP surge, which is reverted by inhibiting ATP mitochondrial export or actin polymerisation. Pharmacological prevention of this confinement-induced nuclear ATP surge impedes cell proliferation through cell cycle defects. Taken together, our data indicates that the physical association between the nucleus and mitochondria is a functional requirement for cell cycle completion after acute mechanical stress.