# Mitochondrial Adaptations Underlying Tetraploidization in Human Cancer, Fungal, and Yeast Models

## TL;DR

This study shows that cells with doubled chromosomes in cancer and yeast have more and more active mitochondria, suggesting mitochondria could be a new target for treating unstable cancers.

## Contribution

The study reveals a conserved mitochondrial adaptation in tetraploid cells across human cancers and yeast models.

## Key findings

- Tetraploid cells from human cancers and yeast models are larger with more mitochondria.
- Mitochondria in tetraploid cells show increased activity and metabolic output.
- Mitochondrial adaptation is identified as a hallmark of tetraploidization.

## Abstract

In many types of cancer, cells double their entire set of chromosomes, a state known as tetraploidy. This change can accelerate the cancer’s growth, spread, and resistance to drugs. We wanted to understand how this chromosome doubling changes the cell’s mitochondria. We compared cells with a normal versus a doubled set of chromosomes from human cancers, yeast, and fungi. We found that in all cases, cells with doubled chromosomes were larger and contained more mitochondria, which were also more active. By identifying this shared trait, our research points to these adapted mitochondria as a potential new target for treating cancers with unstable chromosomes.

Whole-genome duplication, or tetraploidization, occurs in cells, tissues, or entire organisms. In human cancers, tetraploidization promotes aneuploidy and genomic instability, accelerating tumor progression, metastasis, and drug resistance. These adaptations demand metabolic rewiring, including mitochondrial plasticity. Here, we investigate the relationship between mitochondrial quantity/activity, including the mitochondrial transmembrane potential, the intracellular calcium, and the oxidative stress in diploid versus tetraploid cancer cells (colon, sarcoma, liver) and fungal and yeast models (C. albicans diploid/tetraploid strains; S. cerevisiae haploid/diploid/tetraploid strains). We demonstrate that tetraploid cells, whether from human carcinomas or yeast, exhibit consistently enlarged cell size, elevated mitochondrial content, and heightened metabolic activity compared to diploids. Our findings underscore mitochondrial adaptation as a hallmark of tetraploidization, offering novel therapeutic targets for chromosomally unstable tumors.