Retrograde rearrangement of mitochondria correlates with nuclear deformation and genotoxic damage.

The elucidation of molecular mechanisms underlying DNA damage and repair belongs to the fundamental questions of pathophysiology and toxicology. Increasing attention is focusing on the role of mechanical stress exerted on the nucleus and its function as a mechanosensor. Hypothesizing that physical cues arising from the intracellular rearrangements could contribute to the genotoxic damage, we observed that the retrograde relocalization of the mitochondria coincides with increased nuclear stiffness in T24 bladder cells. Perinuclear mitochondrial clustering aligned with the deformation of the nucleus and was accompanied by DNA strand breaks. In the tested experimental layouts, these events appeared scarcely dependent on oxidative stress, strengthening a possible contribution of mechanical nuclear deformation. Proof of principle experiments in SK-OV-3 and HCT 116 cells underpinned the role of cellular architecture and its heterogeneity. These findings open new avenues for understanding how physical changes in the intracellular compartment may drive genotoxicity, potentially supporting genetic instability and carcinogenesis.