# Cancer cells surviving cisplatin chemotherapy increase stress-induced OMA1 activity and mitochondrial fragmentation

## TL;DR

Cancer cells that survive chemotherapy become resistant by changing their mitochondria to handle stress better.

## Contribution

This study reveals a new mechanism of chemotherapy resistance involving OMA1 activity and mitochondrial changes.

## Key findings

- Surviving cancer cells increase OMA1 activity after cisplatin treatment.
- These cells show reduced mitochondrial fusion and function to manage oxidative stress.
- The findings suggest targeting mitochondrial responses could help overcome therapy resistance.

## Abstract

Cancer is one of the leading causes of deaths worldwide. Once cancer cells acquire therapy resistance, they become the main driver of cancer lethality in patients. Thus, mechanisms of therapy resistance must be investigated to improve patient outcomes. Mitochondria are critical organelles in the cellular stress responses, undergoing dynamic morphological and functional changes in response to external stimuli. We and others have identified a chemotherapy-resistant cancer cell state where cells that survive treatment exhibit a dramatic increase in cell size and remain non-proliferative for weeks. In this study, we demonstrate that cancer cells that enter this resistant cell state in response to cisplatin increase OMA1 activity and decrease mitochondrial fusion and function to combat oxidative stress. These findings contribute to further understanding the role of the mitochondrial stress responses in therapy resistance in cancer and provide a potential therapeutic avenue to targeting cancer cells that enter this chemotherapy-resistant cell state.

The online version contains supplementary material available at 10.1038/s41598-025-33677-1.