Mitochondria-derived nuclear ATP surge protects against confinement-induced proliferation defects

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Abstract

The physical microenvironment regulates cell behaviour. However, whether physical confinement rewires the subcellular localisation of organelles and affect metabolism is unknown. Proteomics analysis revealed that cellular confinement induces a strong enrichment of mitochondrial proteins within the nuclear compartment. High-resolution microscopy confirmed that mechanical cell confinement leads to a rapid re-localisation of mitochondria to the nuclear periphery. This nuclear-mitochondrial proximity is mediated by an endoplasmic reticulum-based net that entraps the mitochondria in an actin-dependent manner. Functionally, the mitochondrial proximity results in a nuclear ATP surge, which can be reverted by the pharmacological inhibition of mitochondrial ATP production or via actin depolymerisation. Inhibition of the confinement-derived nuclear ATP surge reveals long-term effects on cell fitness which arise from alterations of chromatin states, delayed DNA damage repair, and impaired cell cycle progression. Together, our data describe a confinement-induced metabolic adaptation that is required to enable prompt DNA damage repair and cell cycle progression by allowing chromatin state transitions.

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