New Research Uncovers Effects of Abnormal Chromosome Numbers on Cell Function

In a groundbreaking study published in *Nature Communications*, researchers from the Rheinland-Pfälzische Technische Universität Kaiserslautern-Landau (RPTU) have detailed the impacts of abnormal chromosome numbers on cellular function, particularly in relation to cancer cells. This research, led by Professor Zuzana Storchová and Dr. Prince Saforo Amponsah, reveals that imbalances in chromosome numbers can significantly disrupt protein balance and mitochondrial function within cells, a finding that has implications for cancer treatment strategies.

The study highlights that healthy human cells typically contain 23 pairs of chromosomes, which must be accurately duplicated and divided during cell division. However, errors in this process can result in aneuploidy, where cells possess an abnormal number of chromosomes. This condition is frequently observed in cancer cells and is also associated with genetic disorders such as Down syndrome. "Even a single extra chromosome can lead to substantial cellular dysfunction, including the overproduction of proteins that interfere with cellular homeostasis," stated Professor Storchová, who heads the Department of Molecular Genetics at RPTU.

Using modified cell lines derived from the colorectal cancer cell line HCT116, the team observed that cells with extra chromosomes accumulated protein aggregates—specifically, sequestosome 1 (SQSTM1, also known as p62)—in their cytoplasm. These aggregates are known to play a role in the recycling of proteins and damaged organelles. Dr. Amponsah noted that the concentration of p62 increased in cells with additional chromosomes, indicating a direct correlation between chromosomal abnormalities and proteomic stress.

Moreover, the researchers discovered that the presence of extra chromosomes altered mitochondrial structure and function. They found that mitochondrial precursor proteins were sequestered by p62-positive aggregates, which impeded their transport into mitochondria. This disruption may contribute to the unique metabolic adaptations observed in cancer cells, allowing them to tolerate proteotoxic stress that would typically be detrimental to normal cells.

The implications of these findings extend beyond basic biology; they suggest that understanding how cancer cells manage mitochondrial metabolism in the face of chromosomal abnormalities could inform new therapeutic strategies. "Our research reveals a previously unknown link between genomic abnormalities, proteotoxic stress, and mitochondrial homeostasis," explained Storchová, emphasizing the potential for these insights to shape future cancer treatments.

This project, entitled "Mitochondrial adaptation to imbalanced nuclear and mitochondrial genome copy numbers," is part of the STRESSistance graduate school program RTG 2737 at RPTU, supported by the German Research Foundation. The collaboration includes contributions from research groups in Kaiserslautern and Munich, involving experts from both institutions. Dr. Amponsah's postdoctoral fellowship was funded by the German Research Foundation's Walter Benjamin Program, showcasing the importance of collaborative research in advancing our understanding of complex biological systems.

As cancer cells navigate the challenges posed by chromosomal abnormalities, their adaptations may contribute to increased drug resistance, a critical hurdle in effective cancer treatment. The research team hopes that their findings will pave the way for innovative approaches to enhance the efficacy of cancer therapies and improve patient outcomes. Looking ahead, the continued exploration of the relationship between genomic stability and cellular function will be vital in combating not only cancer but also other diseases associated with chromosomal instability.