Scientists uncover cancer cells' mitochondrial energy surge under pressure
Researchers have discovered that cancer cells respond to physical squeezing by rapidly deploying mitochondria to the nucleus, delivering a burst of ATP to repair DNA damage and ensure survival. This mechanism, observed in lab experiments and patient biopsies, could inspire new strategies to halt cancer spread. The finding redefines mitochondria's role as dynamic responders rather than static energy sources.
In a study published in Nature Communications, scientists at the Centre for Genomic Regulation in Barcelona revealed how cancer cells activate a defensive energy response when mechanically stressed. Using a specialized microscope to compress living HeLa cells to just three microns wide—about one-thirtieth the diameter of a human hair—researchers observed mitochondria racing to the nucleus within seconds. These organelles form 'NAMs,' or nucleus-associated mitochondria, creating a tight halo that dimples the nucleus inward.
The phenomenon occurred in 84 percent of confined HeLa cells, compared to virtually none in uncompressed ones. A fluorescent sensor showed ATP levels in the nucleus surging by around 60 percent within three seconds of compression. 'It's a clear sign the cells are adapting to the strain and rewiring their metabolism,' says Dr. Fabio Pezzano, co-first author.
This ATP boost is crucial for DNA repair: mechanical squeezing snaps DNA strands and tangles the genome, but the extra energy enables repair crews to mend damage within hours, allowing cells to continue dividing. Without it, cells falter. The mechanism involves actin filaments and the endoplasmic reticulum forming a scaffold to trap mitochondria; treating cells with latrunculin A, which dismantles actin, prevented NAM formation and the ATP surge.
Relevance to cancer was confirmed in breast-tumor biopsies from 17 patients, where NAM halos appeared in 5.4 percent of nuclei at invasive tumor fronts—three times more than the 1.8 percent in dense tumor cores. 'Seeing this signature in patient biopsies convinced us of the relevance beyond the lab bench,' explains Dr. Ritobrata Ghose, co-first author.
The discovery suggests targeting this stress response could make tumors less invasive without harming healthy cells. 'Mechanical stress responses are an underexplored vulnerability of cancer cells that can open new therapeutic avenues,' says Dr. Verena Ruprecht, co-corresponding author. While focused on cancer, the process likely aids other cells under pressure, such as immune cells in lymph nodes or neurons extending branches. 'It forces us to rethink the role of mitochondria... they aren't these static batteries... but more like agile first responders,' notes Dr. Sara Sdelci, co-corresponding author.