Mitochondria-derived nuclear ATP surge protects against mechanical confinement-induced proliferation defects
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ABSTRACT:
PROVIDER: PRJNA1046105 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR26974305_1.fastq.gz | Fastqsanger.gz | |||
| SRR26974305_2.fastq.gz | Fastqsanger.gz | |||
| SRR26974310_1.fastq.gz | Fastqsanger.gz | |||
| SRR26974310_2.fastq.gz | Fastqsanger.gz |
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Project description:The physical microenvironment regulates cell behaviour. Whether physical space constraints reshape the subcellular localisation of organelles and affect metabolism is, however, 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 nucleus-mitochondria 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 the reduction of proximity via actin depolymerisation. Inhibition of this nuclear ATP surge reveals long-term effects on cell fitness and proliferation from DNA damage repair delays and cell cycle defects. Together, our data indicate that physical confinement triggers a metabolic rewiring that enables timely nuclear DNA damage repair and cell cycle progression.
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Project description: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.
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